Current and emerging immunotherapeutic approaches for biliary tract cancers

Background:Biliary tract cancers(BTCs)comprise a heterogeneous group of aggressive malignancies with unfavorable prognoses.The benefit of chemotherapy seems to have reached a bottleneck and,therefore,new effective therapeutic strategies for advanced BTCs are needed.Molecularly targeted therapies in selected patients are rapidly changing the situation.However,the low frequency of specific driver alterations in BTCs limits their wide application.Recently,immunotherapeutic approaches are also under active investigation in BTCs,but the role of immunotherapy in BTCs remains controversial.Data sources:Pub Med,Web of Science,and meeting resources were searched for relevant articles published from January 2017 to May 2022.The search aimed to identify current and emerging immunotherapeutic approaches for BTCs.Information on clinical trials was obtained from https://clinicaltrials.gov/and http://www.chictr.org.cn/.Results:Immunotherapy in BTC patients is currently under investigation,and most of the investigations focused on the application of immune checkpoint inhibitors(ICIs).However,only a subgroup of BTCs with microsatellite-instability high(MSI-H)/DNA mismatch repair-deficient(d MMR)or tumor mutational burden-high(TMB-H)benefit from monotherapy of ICIs,and limited activity was observed in the second or subsequent settings.Nevertheless,promising results come from studies of ICIs in combination with other therapeutic approaches,including chemotherapy,in advanced BTCs,with a moderate toxicity profile.Recent studies demonstrated that compared to GEMCIS alone,durvalumab plus GEMCIS significantly improved patient survival(TOPAZ-1 trial)and that ICIs-combined chemoimmunotherapy is poised to become a new frontline therapy option,regardless of TMB and MMR/MSI status.Adoptive cell therapy and peptide-or dendritic-based cancer vaccines are other immunotherapeutic options that are being studied in BTCs.Numerous biomarkers have been investigated to define their predictive role in response to ICIs,but no predictive biomarker has been validated,except MSI-H/dMMR.Conclusions:The role of immunotherapy in BTCs is currently under investigation and the results of ongoing studies are eagerly anticipated.Several studies have demonstrated the safety and efflcacy of ICIs in combination with chemotherapy in treatment-naive patients,such as the phaseⅢTOPAZ-1 trial,which will change the standard care of first-line chemotherapy for advanced BTCs.However,further research is needed to understand the best combination with immunotherapy and to discover more predictive biomarkers to guide clinical practice.

Potential utility of liquid biopsies in the management of patients with biliary tract cancers:A review

Biliary tract cancer,comprising gallbladder cancer,cholangiocarcinoma and ampullary cancer,represents a more uncommon entity outside high-endemic areas,though global incidence is rising.The majority of patients present at a late stage,and 5-year survival remains poor.Advanced stage disease is incurable,and though palliative chemotherapy has been shown to improve survival,further diagnostic and therapeutic options are required in order to improve patient outcomes.Although certain subtypes of biliary tract cancer are relatively rich in targetable mutations,attaining tumour tissue for histological diagnosis and treatment monitoring is challenging due to locoregional anatomical constraints and patient fitness.Liquid biopsies offer a safe and convenient alternative to invasive procedures and have great potential as diagnostic,predictive and prognostic biomarkers.In this review,the current standard of care for patients with biliary tract cancer,future treatment horizons and the possible utility of liquid biopsies within a variety of contexts will be discussed.Circulating tumour DNA,circulating microRNA and circulating tumour cells are discussed with an overview of their potential applications in management of biliary tract cancer.A summary is also provided of currently recruiting clinical trials incorporating liquid biopsies within biliary tract cancer research.

Immunotherapy in biliary tract cancers:Current evidence and future perspectives

Bile duct tumors are comprised of tumors that originate from both intrahepatic and extrahepatic bile ducts and gallbladder tumors.These are aggressive tumors and chemotherapy is still the main treatment for advanced-stage disease and most of these cases have a poor overall survival.Strategies are aimed at treatments with better outcomes and less toxicity which makes immunotherapy an area of significant importance.Recent Food and Drug Administration approvals of immune checkpoint inhibitors(ICI)for agnostic tumors based on biomarkers such as microsatellite instability-high and tumor mutation burden-high are important steps in the treatment of patients with advanced bile duct tumors.Despite limited responses with isolated checkpoint inhibitors in later lines of systemic treatment in advanced disease,drug combination strategies have been demonstrating encouraging results to enhance ICI efficacy.

Advances in immunotherapy for biliary tract cancers

Biliary tract cancers(BTC),a heterogeneous disease with poor prognosis,including gallbladder cancer(GBC),intrahepatic cholangiocarcinoma(ICC),and extrahepatic cholangiocarcinoma(ECC).Although surgery is currently the primary regimen to treat BTC,most BTC patients are diagnosed at an advanced stage and miss the opportunity of surgical eradication.As a result,non-surgical therapy serves as the main intervention for advanced BTC.In recent years,immunotherapy has emerged as one of the most promising therapies in a number of solid cancers,and it includes immune checkpoint inhibitors(ICIs)monotherapy or combined therapy,tumor vaccines,oncolytic virus immunotherapy,adoptive cell therapy(ACT),and cytokine therapy.However,these therapies have been practiced in limited clinical settings in patients with BTC.In this review,we focus on the discussion of latest advances of immunotherapy in BTC and update the progress of multiple current clinical trials with different immunotherapies.

Clinical and socioeconomic determinants of survival in biliary tract adenocarcinomas

BACKGROUND Despite advances in detection and treatments,biliary tract cancers continue to have poor survival outcomes.Currently,there is limited data investigating the significance of socioeconomic status,race/ethnicity,and environmental factors in biliary tract cancer survival.Data from the Surveillance,Epidemiology,and End Results database for biliary and gallbladder adenocarcinomas were extracted from 1975 to 2016.Socioe-conomic data included smoking,poverty level,education,adjusted household income,and percentage of foreign-born persons and urban population.Survival was calculated with Cox proportional hazards models for death in the 5-year period following diagnosis.RESULTS Our study included 15883 gallbladder,11466 intrahepatic biliary,12869 extrahepatic biliary and 7268 ampulla of Vater adenocarcinoma cases.When analyzing county-specific demographics,patients from counties with higher incomes were associated with higher survival rates[hazard ratio(HR)=0.97,P<0.05].Similarly,counties with a higher percentage of patients with a college level education and counties with a higher urban population had higher 5-year survival rates(HR=0.96,P=0.002 and HR=0.97,P=0.004,respectively).CONCLUSION Worse survival outcomes were observed in lower income counties while higher income and education level were associated with higher 5-year overall survival among gallbladder and biliary malignancies.

Impact of open hepatectomy on postoperative bile leakage in patients with biliary tract cancer

BACKGROUND Bile leakage is a common and serious complication of open hepatectomy for the treatment of biliary tract cancer.AIM To evaluate the incidence,risk factors,and management of bile leakage after open hepatectomy in patients with biliary tract cancer.METHODS We retrospectively analyzed 120 patients who underwent open hepatectomy for biliary tract cancer from February 2018 to February 2023.Bile leak was defined as bile drainage from the surgical site or drain or the presence of a biloma on imaging.The incidence,severity,timing,location,and treatment of the bile leaks were recorded.The risk factors for bile leakage were analyzed using univariate and multivariate logistic regression analyses.RESULTS The incidence of bile leak was 16.7%(20/120),and most cases were grade A(75%,15/20)according to the International Study Group of Liver Surgery classification.The median time of onset was 5 d(range,1-14 d),and the median duration was 7 d(range,2-28 d).The most common location of bile leakage was the cut surface of the liver(70%,14/20),followed by the anastomosis site(25%,5/20)and the cystic duct stump(5%,1/20).Most bile leaks were treated conservatively with drainage,antibiotics,and nutritional support(85%,17/20),whereas some required endoscopic retrograde cholangiopancreatography with stenting(10%,2/20)or percutaneous transhepatic cholangiography with drainage(5%,1/20).Risk factors for bile leakage include male sex,hepatocellular carcinoma,major hepatectomy,blood loss,and blood transfusion.CONCLUSION Bile leakage is a frequent complication of open hepatectomy for biliary tract cancer.However,most cases are mild and can be conservatively managed.Male sex,hepatocellular carcinoma,major hepatectomy,blood loss,and blood transfusion were associated with an increased risk of bile leak.

Phase I study of chimeric antigen receptor modified T cells in treating HER2-positive advanced biliary tract cancers and pancreatic cancers

This phase I clinical trial （NCT01935843） is to evaluate the safety, feasibility, and activity of chimeric antigen receptor-engineered T cell （CART） immunotherapy tar- geting human epidermal growth factor receptor 2 （HER2） in patients with advanced biliary tract cancers （BTCs） and pancreatic cancers （PCs）. Eligible patients with HER2-positive （〉50%） BTCs and PCs were enrolled in the trial. Well cultured CART-HER2 cells were infused following the conditioning treatment composed of nab- paclitaxel （100-200 mg/m2） and cyclophosphamide （15-35 mglkg）. CAR transgene copy number in the peripheral blood was serially measured to monitor the expansion and persistence of CART-HER2 cells in vivo. Eleven enrolled patients received 1 to 2-cycle CART- HER2 cell infusion （median CAR＋ T cell 2.1× 10^6/kg）. The conditioning treatment resulted in mild-to-moderate fatigue, nausea/vomiting, myalgialarthralgia, and lym- phopenia. Except one grade-3 acute febrile syndrome and one abnormal elevation of transaminase （〉9 ULN）, adverse events related to the infusion of CART-HER2 cells were mild-to-moderate. Post-infusion toxicities included one case of reversible severe upper gastroin- testinal hemorrhage which occurred in a patient with gastric antrum invaded by metastasis 11 days after the CART-HER2 cell infusion, and 2 cases of grade 1-2delayed fever, accompanied by the release of C-reactive protein and interleukin-6. All patients were evaluable for assessment of clinical response, among which 1 obtained a 4.5-months partial response and 5 achieved stable disease. The median progression free survival was 4.8 months （range, 1.5-8.3 months）. Finally, data from this study demonstrated the safety and feasibility of CART-HER2 immunotherapy, and showed encourag- ing signals of clinical activity.

Paradigm shift of chemotherapy and systemic treatment for biliary tract cancer

Biliary tract cancers(BTC)are frequently identified at late stages and have a poor prognosis due to limited systemic treatment regimens.For more than a decade,the combination of gemcitabine and cis-platin has served as the first-line standard treatment.There are few choices for second-line chemo-therapy.Targeted treatment with fibroblast growth factor receptor 2 inhibitors,neurotrophic tyrosine receptor kinase inhibitors,and isocitrate dehydrogenase 1 inhibitors has had important results.Immune checkpoint inhibitors(ICI)such as pembrolizumab are only used in first-line treatment for microsatellite instability high patients.The TOPAZ-1 trial's outcome is encouraging,and there are several trials underway that might soon put targeted treatment and ICI combos into first-line options.Newer targets and agents for existing goals are being studied,which may represent a paradigm shift in BTC management.Due to a scarcity of targetable mutations and the higher toxicity profile of the current medications,the new category of drugs may occupy a significant role in BTC therapies.

Horizons on the Therapy of Biliary Tract Cancers:A State-of-theart Review

Biliary tract cancers(BTCs)comprise a group of heterogeneous poor prognosis cancers with increasing incidence recent years.The combination chemotherapy with cisplatin and gemcitabine is the first-line therapy for advanced BTC.There remains no accepted standard treatment in the second-line setting.Nowadays,more and more novel treatment strategies have entered development,with some encouraging results being seen.Here,we review the current treatment status and clinical characteristics of BTC,the role of immunotherapy in BTC as well as the design of clinical trials for oncology drugs for BTC which aim to focus on the future profiles of clinical care and resolution of BTC.

CD98 is a promising prognostic biomarker in biliary tract cancer

ABSTRACT： CD98 has been described to play a crucial role in tumor progression and survival. However, the role of CD98 in biliary tract cancer remains unclear. We found that 36.7% of all patients with biliary tract cancer had a high CD98 expression. Statistical analysis using Spearman＇s rank correlation showed that CD98 was significantly correlated with L-type amino acid transporter 1 （LAT1, r=0.562, P〈0.001）, Ki-67 （r=0.230, P=0.006） and CD34 （r=0.290, P=0.005）. Multivariate analysis confirmed that a high CD98 expression was an independent prognostic factor for predicting poor outcome. CD98 is closely associated with tumor growth, biological aggressiveness, and survival of patients. With these data we proposed that CD98 expression is necessary for the development and pathogenesis of biliary tract cancer.

Biliary tract cancer stem cells-translational options and challenges

Management of biliary tract cancer remains challenging. Tumors show high recurrence rates and therapeutic resistance, leading to dismal prognosis and short survival. The cancer stem cell model states that a tumor is a heterogeneous conglomerate of cells, in which a certain subpopulation of cells-the cancer stem cells-possesses stem cell properties. Cancer stem cells have high clinical relevance due to their potential contributions to development, progression and aggressiveness as well as recurrence and metastasis of malignant tumors. Consequently, reliable identification of as well as pharmacological intervention with cancer stem cells is an intensively investigated and promising research field. The involvement of cancer stem cells in biliary tract cancer is likely as a number of studies demonstrated their existence and the obvious clinical relevance of several established cancer stem cell markers in biliary tract cancer models and tissues. In the present article, we review and discuss the currently available literature addressing the role of putative cancer stem cells in biliary tract cancer as well as the connection between known contributors of biliary tract tumorigenesis such as oncogenic signaling pathways, micro-RNAs and the tumor microenvironment with cancer stem cells.

Inhibitor of differentiation proteins do not influence prognosis of biliary tract cancer

AIM:To investigate the expression and clinical relevance of inhibitor of differentiation(ID)proteins in biliary tract cancer.METHODS:ID protein expression was analyzed in129 samples from patients with advanced biliary tract cancer(BTC)(45 extrahepatic,50 intrahepatic,and 34 gallbladder cancers),compared to normal controls and correlated with clinical an pathological parameters.RESULTS:ID1-3 proteins are frequently overexpressed in all BTC subtypes analyzed.No correlation between increased ID protein expression and tumor grading,tumor subtype or treatment response was detected.Survival was influenced primary tumor localization(extrahepatic vs intrahepatic and gall bladder cancer,OS 1.5 years vs 0.9 years vs 0.7 years,P=0.002),by stage at diagnosis(OS 2.7 years in stageⅠv s 0.6 years in stageⅣ,P<0.001),resection status and response to systemic chemotherapy.In a multivariate model,ID protein expression did not correlate with clinical prognosis.Nevertheless,there was a trend of shorter OS in patients with loss of cytoplasmic ID4 protein expression(P=0.076).CONCLUSION:ID protein expression is frequently deregulated in BTC but does not influence clinical prognosis.Their usefulness as prognostic biomarkers in BTC is very limited.

Combining of chemotherapy with targeted therapy for advanced biliary tract cancer:A systematic review and meta-analysis

BACKGROUND Targeted therapy(TT)has resulted in controversial efficacy as first-line treatment for biliary tract cancer(BTC).More efficacy comparisons are required to clarify the overall effects of chemotherapy(CT)combined with TT and CT alone on advanced BTC.AIM To conduct a meta-analysis of the available evidence on the efficacy of CT combined with TT for advanced BTC.METHODS The PubMed,EMBASE,ClinicalTrials,Scopus and Cochrane Library databases were systematically searched for relevant studies published from inception to August 2022.Only randomized clinical trials(RCTs)including comparisons between the combination of gemcitabine-based CT with TT and CT alone as firstline treatment for advanced BTC were eligible(PROSPERO-CRD42022313001).The odds ratios(ORs)for the objective response rate(ORR)and hazard ratios(HRs)for both progression-free survival(PFS)and overall survival(OS)were calculated and analyzed.Subgroup analyses based on different targeted agents,CT regimens and tumor locations were prespecified.RESULTS Nine RCTs with a total of 1361 individuals were included and analyzed.The overall analysis showed a significant improvement in ORR in patients treated with CT+TT compared to those treated with CT alone(OR=1.43,95%CI:1.11-1.86,P=0.007)but no difference in PFS or OS.Similar trends were observed in the subgroup treated with agents targeting epidermal growth factor receptor(OR=1.67,95%CI:1.17-2.37,P=0.004)but not in the subgroups treated with agents targeting vascular endothelial growth factor receptor or mesenchymal-epithelial transition factor.Notably,patients who received a CT regimen of gemcitabine+oxaliplatin in the CT+TT arm had both a higher ORR(OR=1.75,95%CI:1.20-2.56,P=0.004)and longer PFS(HR=0.83,95%CI:0.70-0.99,P=0.03)than those in the CT-only arm.Moreover,patients with cholangiocarcinoma treated with CT+TT had significantly increased ORR and PFS(ORR,OR=2.06,95%CI:1.27-3.35,PFS,HR=0.79,95%CI:0.66-0.94).CONCLUSION CT+TT is a potential first-line treatment for advanced BTC that leads to improved tumor control and survival outcomes,and highlighting the importance of CT regimens and tumor types in the application of TT.

Risk factors for occult metastasis detected by inflammation-based prognostic scores and tumor markers in biliary tract cancer

BACKGROUND Radiological detection of small liver metastasis or peritoneal metastasis is still difficult,and some patients with biliary tract cancer(BTC)are unresectable after laparotomy.Staging laparoscopy may help avoid unnecessary laparotomy.However,which category of BTC is amenable with staging laparoscopy remains unclear.AIM To clarify the risk factors for occult metastasis in patients with BTC.METHODS Medical records of patients with BTC who underwent surgery at our institution between January 2008 and June 2014 were retrospectively reviewed.The patients were divided into two groups,according to resection or exploratory laparotomy(EL).Preoperative laboratory data,including inflammation-based prognostic scores and tumor markers,were compared between the two groups.Prognostic importance of detected risk factors was also evaluated.RESULTS A total of 236 patients were enrolled in this study.Twenty-six(11%)patients underwent EL.Among the EL patients,there were 16 cases of occult metastasis(7 liver metastases and 9 abdominal disseminations).Serum carcinoembryonic antigen level,carbohydrate antigen 19-9 level,neutrophil-lymphocyte ratio and modified Glasgow prognostic score were significantly higher in the EL group than in the resected group,and these factors were prognostic.Among these factors,carcinoembryonic antigen>7 ng/mL was the most useful to predict occult metastasis in BTC.When patients have more than three of these positive factors,the rate of occult metastasis increases.CONCLUSION Inflammation-based prognostic scores and tumor markers are useful in detecting occult metastasis in BTC;based on these factors,staging laparoscopy may reduce the rate of EL.

Efficacy and Safety of Chemotherapy with or without Targeted Therapy in Biliary Tract Cancer:A Meta-analysis of 7 Randomized Controlled Trials

The systematic treatment based on gemcitabine plus cisplatin is recommended as the current standard chemotherapy for unresectable or metastatic biliary tract cancers.However,the exact benefits from the recognized regime are still dismal.We thus elicit this study in an attempt to analyze whether targeted therapy coupled with various chemotherapy could produce improvement of survival benefits.The clinical trials were searched electronically from databases till July 2016 published in English and Chinese.Nine hundred and sixty-four patients from 7 trials were identified in our analysis.The overall analysis achieved a significantly higher overall response rate（ORR） among the patients treated with targeted drugs plus chemotherapy than chemotherapy alone（OR=1.87;95% CI：1.37–2.57;P=0.000）,but failed in the overall progression-free survival（PFS） [mean difference（MD）=0.63;95% CI：–0.45–1.72;P=0.26] and overall survival（OS）（MD=–0.67;95% CI：–2.54–1.20;P=0.49）.In the sub analysis,better ORR was obtained with the addition of EGFR（OR=1.75;95% CI：1.20–2.56;P=0.004） and VEGFR（OR=2.5;95% CI：1.28–4.87;P=0.007） targeted therapy.Furthermore,the sub analysis of EGFR target showed an significant improvement on PFS（MD=1.36;95% CI：0.29–2.43;P=0.01）.No significant differences were observed in the incidences of neutropenia（OR=1.37;95% CI：0.89–2.12）,thrombocytopenia（OR=1.40;95% CI：0.83–2.39）,anemia（OR=1.21;95% CI：0.62–2.38）,peripheral neuropathy（OR=1.52;95% CI：0.81–2.88）,increased AST/ALT（OR=1.40;95% CI：0.82–2.39） as well as fatigue（OR=1.65;95% CI：0.96–2.84） in either of the treatment groups.In conclusion,better ORR associated with chemotherapy combined with targeted therapy（both targeting EGFR and VEGF） is found in the present meta-analysis without the cost of increased unacceptable toxicities,but regretfully not for the OS.The sub-analysis of targeting EGFR instead of VEGF obtains a superior PFS.Otherwise,there is no statistically significant difference in the overall PFS between the combination regime and chemotherapy alone.Given the paucity of favorable data,we need further studies to characterize optimal targeted agents to confirm the potential value to biliary tract cancer.

Biomarkers for response to immunotherapy in hepatobiliary malignancies

Background:The advent of immune checkpoint inhibitors(ICIs)has revolutionized the therapeutic options of hepatobiliary malignancies.However,the clinical benefit provided by immunotherapy seems limited to a small subgroup of patients with hepatobiliary malignancies.The identification of reliable predictors of the response to immunotherapy is urgently needed.Data sources:Literature search was conducted in Pub Med for relevant articles published up to May 2022.Information of clinical trials was obtained from https://clinicaltrials.gov/.Results:Biomarkers for ICI response of hepatobiliary malignancies remain in the exploration stage and lack compelling evidence.Tumor programmed death-ligand 1(PD-L1)expression is the most widely studied biomarker in hepatocellular carcinoma(HCC)and biliary tract cancers(BTCs),but there are conflicting results on its predictive potential.Tumor mutational burden(TMB)is generally low both in HCC and BTCs,and the clinical trials of TMB are rare in hepatobiliary malignancies.Promisingly,mismatch repair deficiency(dMMR)/high microsatellite instability(MSI-H)may be a predictive biomarker of response to antiPD-1 therapy in BTCs.Furthermore,some emerging biomarkers,such as gut microbiota,show predictive potential in the preliminary studies.Radiomics and liquid-biopsy biomarkers,including circulating tumor cells,circulating tumor DNA(ct DNA)and exosomal PD-L1 provide a quick and non-invasive approach for monitoring the ICI response,showing a new promising direction.Conclusions:Multiple potential biomarkers for predicting ICI response of hepatobiliary malignancies have been explored and tried to apply in clinic.Yet there is no robust evidence to prove their clinical value in predicting immunotherapeutic response for patients with hepatobiliary malignancies.The identification of predictors for response to ICIs is an urgent need and major challenge.Further studies are warranted to validate the role of emerging biomarkers in predicting immunotherapeutic responses.

Association between gut microbiota and hepatocellular carcinoma and biliary tract cancer:A mendelian randomization study

BACKGROUND An increasing number of studies have begun to discuss the relationship between gut microbiota and diseases,yet there is currently a lack of corresponding articles describing the association between gut microbiota and hepatocellular carcinoma(HCC)and biliary tract cancer(BTC).This study aims to explore the relationship between them using Mendelian randomization(MR)analysis method.AIM To assess the relationship between gut microbiota and HCC and BTC.METHODS We obtained Genome-wide association study(GWAS)data for the gut microbiome from the intestinal microbiota genomic library(MiBioGen,https://mibiogen.gcc.rug.nl/).Additionally,we accessed data pertaining to HCC and BTC from the IEU open GWAS platform(https://gwas.mrcieu.ac.uk/).Our analysis employed fundamental instrumental variable analysis methods,including inverse-variance weighted,MR and Egger.To ensure the dependability of the results,we subjected the results to tests for multiple biases and heterogeneity.RESULTS During our investigation,we discovered 11 gut microbiota linked to an increased risk to BTC and HCC.The former included the genus Eubacterium hallii group(P=0.017),Candidatus Soleaferrea(P=0.034),Flavonifractor(P=0.021),Lachnospiraceae FCS020(P=0.034),the order Victivallales(P=0.018),and the class Lentisphaeria(P=0.0.18).The latter included the genus Desulfovibrio(P=0.042),Oscillibacter(P=0.023),the family Coriobacteriaceae(P=0.048),the order Coriobacteriales(P=0.048),and the class Coriobacteriia(P=0.048).Furthermore,in BTC,we observed 2 protective gut microbiota namely the genus Dorea(P=0.041)and Lachnospiraceae ND3007 group(P=0.045).All results showed no evidence of multiplicity or heterogeneity.CONCLUSION This study explores a causal link between gut microbiota and HCC and BTC.These insights may enhance the mechanistic knowledge of microbiota-related HCC and BTC pathways,potentially informing therapeutic strategies.

Combination Therapies for Advanced Biliary Tract Cancer

Biliary tract cancers(BTCs)are a group of malignant neoplasms that have recently increased in incidence and have a poor prognosis.Surgery is the only curative therapy.However,most patients are only indicated for palliative therapy because of advanced-stage disease at diagnosis and rapid progression.The current first-line treatment for advanced BTC is gemcitabine and cisplatin chemotherapy.Nonetheless,many patients develop resistance to this regimen.Over the years,few chemotherapy regimens have managed to improve the overall survival of patients.Accordingly,novel therapies such as targeted therapy have been introduced to treat this patient population.Extensive research on tumorigenesis and the genetic profiling of BTC have revealed the heterogenicity and potential target pathways,such as EGFR,VEGF,MEK/ERK,PI3K and mTOR.Moreover,mutational analysis has documented the presence of IDH1,FGFR2,HER2,PRKACA,PRKACB,BRAF,and KRAS gene aberrations.The emergence of immunotherapy in recent years has expanded the treatment landscape for this group of malignancies.Cancer vaccines,adoptive cell transfer,and immune checkpoint inhibitors have been extensively investigated in trials of BTC.Therefore,patient stratification and a combination of various therapies have become a reasonable and important clinical strategy to improve patient outcomes.This review elaborates the literature on combined treatment strategies for advanced BTC from the past few years and ongoing clinical trials to provide new inspiration for the treatment of advanced BTC.

Cohort study to assess geographical variation in cholangiocarcinoma treatment in England

BACKGROUND Outcomes for cholangiocarcinoma(CCA)are extremely poor owing to the complexities in diagnosing and managing a rare disease with heterogenous sub-types.Beyond curative surgery,which is only an option for a minority of patients diagnosed at an early stage,few systemic therapy options are currently recommended to relieve symptoms and prolong life.Stent insertion to manage disease complications requires highly specialised expertise.Evidence is lacking as to how CCA patients are managed in a real-world setting and whether there is any variation in treatments received by CCA patients.AIM To assess geographic variation in treatments received amongst CCA patients in England.METHODS Data used in this cohort study were drawn from the National Cancer Registration Dataset(NCRD),Hospital Episode Statistics and the Systemic Anti-Cancer Therapy Dataset.A cohort of 8853 CCA patients diagnosed between 2014-2017 in the National Health Service in England was identified from the NCRD.Potentially curative surgery for all patients and systemic therapy and stent insertion for 7751 individuals who did not receive surgery were identified as three end-points of interest.Linear probability models assessed variation in each of the three treatment modalities according to Cancer Alliance of residence at diagnosis,and for socio-demographic and clinical characteristics at diagnosis.RESULTS Of 8853 CCA patients,1102(12.4%)received potentially curative surgery.The mean[95%confidence interval(CI)]percentage-point difference from the population average ranged from-3.96(-6.34 to-1.59)%to 3.77(0.54 to 6.99)%across Cancer Alliances in England after adjustment for patient sociodemographic and clinical characteristics,showing statistically significant variation.Amongst 7751 who did not receive surgery,1542(19.9%)received systemic therapy,with mean[95%CI]percentage-point difference from the population average between-3.84(-8.04 to 0.35)%to 9.28(1.76 to 16.80)%across Cancer Alliances after adjustment,again showing the presence of statistically significant variation for some regions.Stent insertion was received by 2156(27.8%),with mean[95%CI]percentage-point difference from the population average between-10.54(-12.88 to-8.20)%to 13.64(9.22 to 18.06)%across Cancer Alliances after adjustment,showing wide and statistically significant variation from the population average.Half of 8853 patients(n=4468)received no treatment with either surgery,systemic therapy or stent insertion.CONCLUSION Substantial regional variation in treatments received by CCA patients was observed in England.Such variation could be due to differences in case-mix,clinical practice or access to specialist expertise.

Guidelines for hepatobiliary cancers:treatment strategies in the East and West

Hepatocellular carcinoma(HCC)is the most common type of primary liver cancer originating from hepatocytes,whereas intrahepatic cholangiocarcinoma(ICC)occurs in parts of the bile ducts within the liver and is the second most common primary malignant liver tumor.Extrahepatic cholangiocarcinoma develops in the bile ducts outside the liver and includes hilar and distal bile duct cancers.