Adjuvant and neoadjuvant therapy for biliary tract cancer: a review of clinical trials.

Cancer originating in the biliary tract can be classified as bile duct cancer (cholangiocarcinoma), gallbladder cancer, or ampullary cancer. Bile duct cancer is further divided to intrahepatic, perihilar and distal bile duct subtypes according to the anatomical location of the tumor. The biological characteristics of each tumor are heterogeneous. However, because of the rarity of each disease, the efficacy of new drugs has been tested in groups of patients with different biliary tract cancers. In patients with metastatic or recurrent biliary tract cancer, recent randomized clinical trials revealed the non-inferiority of gemcitabine + S-1 and the superiority of gemcitabine + cisplatin + S-1 compared with gemcitabine + cisplatin in terms of overall survival, thereby establishing a new standard treatment. In the field of adjuvant therapy for biliary tract cancer, the British BILCAP (capecitabine compared with observation in resected biliary tract cancer) study revealed longer median overall survival in the capecitabine group than in the observation group in the per-protocol analysis (but not in the intention-to-treat analysis), bringing a shift toward postoperative management. Several other studies of adjuvant therapy are ongoing, and they may lead to reforms in treatment strategy for resectable biliary tract cancer in the future. The use of neoadjuvant therapy for biliary tract cancer is in its infancy, but it is expected to overcome the limitations of adjuvant therapy for this malignancy. In this review, we summarized the evidence available from clinical trials of adjuvant and neoadjuvant therapy for biliary tract cancer and described ongoing clinical trials.

Statin use and reduced risk of biliary tract cancers in the UK Clinical Practice Research Datalink.

OBJECTIVE: To evaluate the association between statin use and risk of biliary tract cancers (BTC). DESIGN: This is a nested case-control study conducted in the UK Clinical Practice Research Datalink. We included cases diagnosed with incident primary BTCs, including cancers of the gall bladder, bile duct (ie, both intrahepatic and extrahepatic cholangiocarcinoma), ampulla of Vater and mixed type, between 1990 and 2017. For each case, we selected five controls who did not develop BTCs at the time of case diagnosis, matched by sex, year of birth, calendar time and years of enrolment in the general practice using incidence density sampling. Exposures were defined as two or more prescription records of statins 1 year prior to BTC diagnosis or control selection. ORs and 95% CIs for associations between statins and BTC overall and by subtypes were estimated using conditional logistic regression, adjusted for relevant confounders. RESULTS: We included 3118 BTC cases and 15 519 cancer-free controls. Current statin use versus non-use was associated with a reduced risk of all BTCs combined (adjusted OR=0.88, 95% CI 0.79 to 0.98). The reduced risks were most pronounced among long-term users, as indicated by increasing number of prescriptions (ptrend=0.016) and cumulative dose of statins (ptrend=0.008). The magnitude of association was similar for statin use and risk of individual types of BTCs. The reduced risk of BTCs associated with a record of current statin use versus non-use was more pronounced among persons with diabetes (adjusted OR=0.72, 95% CI 0.57 to 0.91). Among non-diabetics, the adjusted OR for current statin use versus non-use was 0.91 (95% CI 0.81 to 1.03, pheterogeneity=0.007). CONCLUSION: Compared with non-use of statins, current statin use is associated with 12% lower risk of BTCs; no association found with former statin use. If replicated, particularly in countries with a high incidence of BTCs, our findings could pave the way for evaluating the value of statins for BTC chemoprevention.

Clinicopathological characteristics of biliary neuroendocrine neoplasms: a multicenter study.

OBJECTIVES: This study assessed the clinicopathological features, therapeutic approaches, and prognosis of patients with biliary neuroendocrine neoplasm (NENs). MATERIALS AND METHODS: Multicenter retrospective study of patients with biliary tract NENs in the gallbladder, the extrahepatic bile duct, or the ampulla of Vater between 2005 and 2014. RESULTS: Total of 43 patients were included in the study. The median age was 62 years (range: 29-84 years) and 58.1% of the patients were male. The tumors occurred in the gallbladder (n = 11), the extrahepatic bile duct (n = 5) or the ampulla of Vater (n = 27). The liver was the most common metastatic site. Based on the 2010 World Health Organization classification, more patients with gallbladder NENs (11/11 (100%)) had neuroendocrine carcinoma G3 than those with NENs in the ampulla of Vater (10/27 (37.1%)). The median progression free survival time (39.3 vs 5.1 months, p = 0.001) and median overall survival time (46.9 vs 7.9 months, p < 0.001) were significantly longer in patients with ampulla of Vater NENs than gallbladder NENs. A 2010 World Health Organization classification of neuroendocrine carcinoma G3 was independently related to poor overall survival (hazard ratio (HR), 27.1; 95% confidence intervals (CI), 2.81-260.68; p = 0.004). CONCLUSION: The 2010 World Health Organization classification of neuroendocrine carcinoma G3 was the only factor related to poor prognosis in patients with biliary neuroendocrine neoplasms.

Pathologic staging of pancreatic, ampullary, biliary, and gallbladder cancers: pitfalls and practical limitations of the current AJCC/UICC TNM staging system and opportunities for improvement.

Tumors of the ampulla-pancreatobiliary tract are encountered increasingly; however, their staging can be highly challenging due to lack of familiarity. In this review article, the various issues encountered in staging of these tumors at the pathologic level are evaluated and possible solutions for daily practice as well as potential improvements for future staging protocols are discussed. While N-stage parameters have now been well established (the number of lymph nodes required in pancreatoduodenectomies is 12), the T-staging has several issues: for the pancreas, the discovery of small cancers arising in intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) necessitates the creation of substages of T1 (as T1a, b, and c); lack of proper definition of "peripancreatic soft tissue" and "common bile duct involvement" (as to which part is meant) makes T3 highly subjective. Increasing resectability of main vessels (portal vein) brings the need to redefine a "T" for such cases. For the ampulla, due to factors like anatomic complexity of the region and the under-appreciation of three-dimensional spread of the tumors in this area (in particular, the frequent extension into periduodenal soft tissues and duodenal serosa, which are not addressed in the current system and which require specific grossing approaches to document), the current T-staging lacks reproducibility and clinical relevance, and therefore, major revisions are needed. Recently proposed refined definition and site-specific subclassification of ampullary tumors highlight the areas for improvement. For the extrahepatic bile ducts, the staging schemes that use the depth of invasion may be more practical to circumvent the inconsistencies in the histologic layering of the ducts; better definition of terms like "periductal spread" is needed. For the gallbladder, since many gallbladder cancers are "unapparent" (found in clinically and grossly unsuspected cholecystectomies), establishing proper grossing protocols and adequate sampling are crucial. Since the gallbladder does not have the distinct layering of the other gastrointestinal organs, the definitions of Tis/T1a/T1b lack practicality, and therefore, "early gallbladder carcinoma" category proposed in high-risk regions may have to be recognized instead. Involvement of the Rokitansky-Aschoff sinuses should be a part of the evaluation and management of these early gallbladder cancers; for advanced cancers, documentation of hepatic versus serosal involvement is necessary. In summary, T-staging of ampulla-pancreatobiliary tract tumors has many challenges. Proper grossing and appreciation of histo-anatomic subtleties of this region are crucial in addressing these issues and achieving more applicable and clinically relevant staging systems in the future.

Diagnosis and treatment update: cholangiocarcinoma.

Cholangiocarcinoma is a rare and very aggressive neoplasm that arises from the biliary epithelium, constitutes approximately 2% of all reported cancer, and accounts for about 3% of all gastrointestinal malignancies. Up to date, there are many modalities to diagnosis and treat with a range of sensitivity and specificity, and also the advantage and disadvantage of its modality. As a physician, we should be able to assess and choose promptly which modality is best for our patient, even for paliative care. Treatment modalities are surgery and non-surgery like adjuvant chemotherapy, radiation, chemoradiation, radiotherapy, TACE, 5-FU chemoinfusion, intralesion PEI, photodynamic therapy, liver transplantation, and paliative therapy. The choice of treatment varies individually. Radical surgery remains the optimal therapy and offering a potential for cure. Overall prognosis in these patients is poor and survival is limited to a few months.

Artificial neural networks for multi-omics classifications of hepato-pancreato-biliary cancers: towards the clinical application of genetic data.

PURPOSE: Several multi-omics classifications have been proposed for hepato-pancreato-biliary (HPB) cancers, but these classifications have not proven their role in the clinical practice and been validated in external cohorts. PATIENTS AND METHODS: Data from whole-exome sequencing (WES) of The Cancer Genome Atlas (TCGA) patients were used as an input for the artificial neural network (ANN) to predict the anatomical site, iClusters (cell-of-origin patterns) and molecular subtype classifications. The Ohio State University (OSU) and the International Cancer Genome Consortium (ICGC) patients with HPB cancer were included in external validation cohorts. TCGA, OSU and ICGC data were merged, and survival analyses were performed using both the 'classic' survival analysis and a machine learning algorithm (random survival forest). RESULTS: Although the ANN predicting the anatomical site of the tumour (i.e. cholangiocarcinoma, hepatocellular carcinoma of the liver, pancreatic ductal adenocarcinoma) demonstrated a low accuracy in TCGA test cohort, the ANNs predicting the iClusters (cell-of-origin patterns) and molecular subtype classifications demonstrated a good accuracy of 75% and 82% in TCGA test cohort, respectively. The random survival forest analysis and Cox' multivariable survival models demonstrated that models for HPB cancers that integrated clinical data with molecular classifications (iClusters, molecular subtypes) had an increased prognostic accuracy compared with standard staging systems. CONCLUSION: The analyses of genetic status (i.e. WES, gene panels) of patients with HPB cancers might predict the classifications proposed by TCGA project and help to select patients suitable to targeted therapies. The molecular classifications of HPB cancers when integrated with clinical information could improve the ability to predict the prognosis of patients with HPB cancer.

Translating cancer genomics for precision oncology in biliary tract cancers.

Biliary tract cancers (BTC), which include cholangiocarcinoma (both intra- and extrahepatic) and gallbladder, represent a heterogeneous group of malignancies with relatively low-incidence and poor prognosis. Therapeutic options for BTC patients at advanced stage are severely limited and palliative chemotherapy remains the maintreatment option. In the past decade, genome profiling via next-generation sequencing of large international cohorts has paved the way for precision oncology in BTC, identifying unique molecular subtypes, recurrent mutations, and genomic rearrangements. Targeted therapies directed against some of these aberrations are currently under investigation in phase 3 clinical studies and hold great promise to improve the prognosis of this disease. Thus, in the near term, the individual molecular alterations of the disease rather than the anatomic location will likely drive the design of clinical trials. In this review, we summarize recent molecular discoveries in BTC with a special emphasis on the most promising therapeutic targets, ultimately providing an update on current and future directions in the management of this disease.

Staging of Biliary and Primary Liver Tumors: Current Recommendations and Workup.

Hepatobiliary malignancies are a diverse group of neoplasms involving the liver, gallbladder, and bile ducts. Although intrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma, hepatocellular carcinoma, and gallbladder adenocarcinoma share many biological and anatomic features, they have distinct clinical presentations and natural histories that require individual consideration. Here, we discuss the incidence, outcomes, patient presentation, initial workup, pathologic diagnoses, staging classification, imaging and surgical staging, and determinants of resectability for each malignancy.

Bile cell­free DNA as a novel and powerful liquid biopsy for detecting somatic variants in biliary tract cancer.

Tissue sampling of biliary tract carcinomas (BTCs) for molecular characterization is challenging. The aim of this study was to investigate the possibility of identifying individual actionable mutations derived from bile cell­free DNA (cfDNA) using targeted deep sequencing. Ten BTC patients, four with gallbladder carcinomas and six with cholangiocarcinomas, were enrolled in the present study. Using targeted deep sequencing with a panel of 150 tumor­related genes, paired bile cfDNA and tumor DNA were analyzed for mutational variants individually and then compared. The present study, to the best of our knowledge, is the first to reveal that bile cfDNA is predominantly comprised of long DNA fragments, which is not the case for plasma cfDNA. Herein, paired bile cfDNA and tumors from ten BTC patients were examined using targeted deep sequencing. When comparing bile cfDNA and tumor DNA for single nucleotide variation (SNV)/insertion and deletion (Indel), the results using targeted deep sequencing revealed high sensitivity (94.7%) and specificity (99.9%). Additionally, the sensitivity of detecting a copy number variation (CNV) was 75.0%, with a specificity of 98.9%. When comparing two bile extraction methods, including percutaneous transhepatic cholangial drainage and operation, no significant difference in SNV/Indel or CNV detection sensitivity was noted. Moreover, when examining the tumor stage and incidence site, AJCC stage II and the distal bile duct both had significantly decreased CNV detection sensitivities. The present study revealed that targeted deep sequencing can reliably detect mutational variants within bile cfDNA obtained from BTC patients. These preliminary results may shed light on bile cfDNA as a promising liquid biopsy for BTC patients.

The A.L.A.N. score identifies prognostic classes in advanced biliary cancer patients receiving first-line chemotherapy.

BACKGROUND: Chemotherapy is the mainstay treatment for advanced biliary cancer (ABC). Best supportive care and clinical trials are currently alternative options. The identification of a prognostic score that can be widely applied to daily practice has the potential to better inform clinical management of ABC patients. METHODS: A cohort of 123 ABC patients undergoing first-line chemotherapy was used as an exploratory cohort to define the prognostic value of laboratory tests routinely performed in clinical practice. Kaplan-Meier analysis was used to investigate the association between the variables and overall survival (OS). Those variables that were statistically significant at the multivariate analysis were combined in a multiplex score. Performance of the novel prognostic score was confirmed in a validation cohort of 60 ABC patients. RESULTS: Baseline actual neutrophil count, lymphocytes-monocytes ratio, neutrophil-lymphocytes ratio and albumin (A.L.A.N.) correlated with OS at the multivariate analysis in the exploratory cohort. When combined in the multiplex, A.L.A.N. score was able to identify three classes of ABC patients with significantly different OS (high-risk: median OS, 5 months; intermediate-risk: median OS, 12 months and low-risk: median OS, 22 months; p:<0.001). The score performed well in the different subtypes of ABC and was independent of stage, performance status and chemotherapy regimen. The performance of the A.L.A.N. score was confirmed in a validation cohort of cholangiocarcinoma patients (high-risk: median OS, 4.3 months; intermediate-risk: median OS 9.3 months, low-risk: median OS 13 months; p:0.005). CONCLUSIONS: The A.L.A.N score can be derived by variables routinely recorded in clinical practice and can provide prognostic assessment of ABC patients considered for first-line treatment.

Adjuvant Therapy for Biliary Tract Cancers.

Biliary tract cancers, including gallbladder cancer, intrahepatic, perihilar, and distal cholangiocarcinomas, although anatomically contiguous, represent a heterogeneous group of cancers with extensive biologic and genetic diversity. With early disease, surgical resection is the preferred option for all subtypes; however, relapse rates remain high, and survival outcomes are poor. Data to guide the use of adjuvant therapy have been limited to retrospective series, population-based studies, and meta-analyses, all with their associated limitations. The number of prospective trials ongoing or completed is increasing, and these results will ultimately dictate optimal treatment of this group of diseases. This review summarizes the data for adjuvant therapy in biliary tract cancers.

Classification of biliary tract cancers established by the Japanese Society of Hepato-Biliary-Pancreatic Surgery: 3(rd) English edition.

The 3(rd) English edition of the Japanese classification of biliary tract cancers was released approximately 10 years after the 5(th) Japanese edition and the 2(nd) English edition. Since the first Japanese edition was published in 1981, the Japanese classification has been in extensive use, particularly among Japanese surgeons and pathologists, because the cancer status and clinical outcomes in surgically resected cases have been the main objects of interest. However, recent advances in the diagnosis, management and research of the disease prompted the revision of the classification that can be used by not only surgeons and pathologists but also by all clinicians and researchers, for the evaluation of current disease status, the determination of current appropriate treatment, and the future development of medical practice for biliary tract cancers. Furthermore, during the past 10 years, globalization has advanced rapidly, and therefore, internationalization of the classification was an important issue to revise the Japanese original staging system, which would facilitate to compare the disease information among institutions worldwide. In order to achieve these objectives, the new Japanese classification of the biliary tract cancers principally adopted the 7(th) edition of staging system developed by the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC). However, because there are some points pending in these systems, several distinctive points were also included for the purpose of collection of information for the future optimization of the staging system. Free mobile application of the new Japanese classification of the biliary tract cancers is available via http://www.jshbps.jp/en/classification/cbt15.html.

Improved survival in resected biliary malignancies.

BACKGROUND: For many years the prognosis for patients with biliary malignancies has been poor. However, recent advances in radiology and laparoscopy have improved staging, and active biliary stent management may improve outcome in these patients. In the past the goal with surgery was to excise all gross tumor. Now, the surgical goal is to achieve negative microscopic margins even if a major hepatic resection is required. Similarly, chemotherapy or radiation was frequently given in isolation, but chemoradiation has become the standard. Therefore, the aim of this analysis was to determine whether survival has improved with better staging, active stent management, more aggressive surgery, and chemoradiation. METHODS: From 1990 through 2001, 140 patients with biliary malignancies were treated at the Medical College of Wisconsin. One hundred eleven malignancies were cholangiocarcinomas (intrahepatic, 22%; perihilar, 65%; and distal, 13%), and 29 were gallbladder (GB) cancers. Eighty-six of the 140 patients (61%) underwent exploration (intrahepatic, 58%; perihilar, 57%; distal, 67%, and GB, 72%). Forty-four of these 86 patients (51%) underwent resection (intrahepatic, 64%; perihilar, 41%; distal, 70%; and GB, 52%). Chemoradiation with confocal radiation, 5-fluorouracil, and gemcitabine was used more frequently in the patients resected since 1998. RESULTS: Thirty-day operative mortality was 4%. In the resected patients (n = 44) the 5-year actuarial survival was 31% and the median survival was 27.8 months. Patients resected between 1998 and 2001 (n = 25) had a median survival longer than 44 months with a 3-year actuarial survival of 70% as compared to patients resected between 1990 and 1997 (n = 19), who had a median survival of 13 months and a 3-year actuarial survival of 21% (P <.01). CONCLUSIONS: These data suggest that (1) approximately one third of patients with biliary malignancies have resectable disease and (2) surgery in carefully selected patients with adjuvant chemoradiation has improved survival in resected patients. We suspect that a combination of improved staging, active biliary stenting, safe but extensive surgery to obtain negative margins, and newer techniques for chemoradiation have resulted in improved outcomes for patients with biliary malignancies.

Cytokeratin 5/6 immunostaining in hepatobiliary and pancreatic neoplasms.

Immunohistochemistry with different cytokeratin subsets has been successfully used in the differential diagnosis of various human epithelial neoplasms. Cytokeratin 5/6 antibody, which recently became commercially available, has been found useful in the diagnosis of mesothelioma. Studies have reported only infrequent staining in adenocarcinomas. We investigated the pattern of immunoreactivity for cytokeratin 5/6 in hepatobiliary and pancreatic tumors to determine its diagnostic utility in the morphologic evaluation of these neoplasms. Formalin-fixed. paraffin-embedded tissue sections from 10 hepatocellular carcinomas, seven hepatocellular adenomas, 10 cholangiocarcinomas, 10 pancreatic ductal adenocarcinomas, and 13 pancreatic neuroendocrine carcinomas were immunostained with anticytokeratin 5/6 after heat-induced antigen retrieval utilizing a modified avidin-biotin complex technique. Positive and negative controls stained appropriately. Two pathologists evaluated the slides. Strong but focal cytoplasmic immunoreactivity was observed in five of 10 pancreatic ductal adenocarcinomas and two of 10 cholangiocarcinomas. No immunoreactivity was identified in any cases of hepatocellular carcinoma (0/10), hepatocellular adenoma (0/7), or pancreatic neuroendocrine carcinoma (0/13). Additionally, occasional cytokeratin 5/6 immunoreactive benign ductal epithelial cells were seen in the background in some cases. Fifty percent of pancreatic ductal adenocarcinomas and 20% of cholangiocarcinomas are positive with anti-cytokeratin 5/6 immunostaining. For the evaluation of poorly differentiated neoplasms in the liver, immunoreactivity with cytokeratin 5/6 may help to exclude the possibility of hepatocellular carcinoma. Cytokeratin 5/6 may be helpful as a component in the panel of immunostains to differentiate between poorly differentiated neoplasms.

Reclassification of "atypical" diagnoses in endoscopic retrograde cholangiopancreaticography-guided biliary brushings.

OBJECTIVE: To evaluate the usefulness of reclassifying "atypical" diagnoses in reporting biliary cytology using strict morphologic criteria. STUDY DESIGN: Cytologic specimens from 139 patients (direct, alcohol-fixed smears or cytocentrifuge preparations) were evaluated. Diagnoses were benign (70), atypical (36) and malignant (33). Using strict criteria--major (nuclear contour, chromatin pattern) and minor (polarity, cell types, nuclear size, nuclear grooves, nucleoli, mitosis, nuclear/cytoplasmic [N/C] ratio)--atypical cases were reevaluated and reclassified. Follow-up (F/U) was available on all cases. RESULTS: Atypical cases, (36) were reclassified as malignant (26), atypical favor benign (2)/reactive (3) and atypical, not otherwise specified (NOS) (5). Cases reclassified as malignant showed irregular nuclear contours, chromatin irregularities and rare mitosis. Nuclear enlargement, nucleoli and cellularity varied widely in all groups. N/C ratio was increased in most reclassified malignant cases. All 26 malignant reclassifications correlated with F/U of malignancy. Benign and reactive cases (5) were negative for malignancy on F/U (4), and in 1 case a metastatic carcinoma involving the biliary tree was found. In the 5 atypical (NOS) cases, F/U showed malignancy (3) and pancreatitis (2). Cytocentrifuge preparations made in our laboratory were of superior quality when compared to other methods of cell preparation. CONCLUSION: Irregularities in nuclear membrane and abnormal chromatin pattern were the most consistently useful features correlating with malignancy. The sensitivity and specificity of biliary brush cytology can be enhanced by using strict cytomorphologic criteria and proper collection and fixation, all of which decrease atypical diagnoses.