Optimum chemotherapy for the management of advanced biliary tract cancer

Biliary tract cancers(BTCs) are highly fatal malignancies, which are often diagnosed at an advanced stage and have relatively poor prognosis.The treatment of patients with advanced BTC is systemic, based on chemotherapy or best supportive care, depending on their performance status.Despite clinical trials studyingmany chemotherapeutic regimens and targeted therapies for the treatment of BTC, the standard of care for advanced BTC remains the combination of gemcitabine with cisplatin.Many new molecules targeting proliferation and survival pathways, the immune response and angiogenesis are currently undergoing phase Ⅰ and Ⅱ trials for the treatment of advanced BTC with promising results.     

Development of molecularly targeted therapies in biliary tract cancers: reassessing the challenges and opportunities

Biliary tract cancers (BTCs), which encompass intra- and extrahepatic cholangiocarcinomas as well as gallbladder carcinomas, are a genetically diverse collection of cancers. Most patients with BTC will present with unresectable or metastatic disease. Although the standard systemic chemotherapy approaches are emerging, the prognosis remains poor. Development of molecularly targeted therapies in advanced BTC remains challenging. Recent early-stage clinical trials with targeted therapies appear promising, although the relationships between subsets of patients with positive responses to therapy and tumor genetics remain unexplored. Here we summarize the relevant molecular pathogenesis, recent and ongoing clinical trials with targeted agents, and the key issues in clinical trial design in BTC.     

分子靶向治疗晚期胆系恶性肿瘤的研究进展

胆系恶性肿瘤(BTC)是起源于肝内外胆管及胆囊壁黏膜上皮细胞恶性肿瘤,约占消化系统恶性肿瘤的3％,近年来发病率和病死率不断增加.基于临床和病理异质性的特点,BTC早期发现困难,确诊时往往已处于晚期,预后极差.一直以来,晚期BTC都是唯化学治疗,但治疗效果不尽如人意.近年来,随着精准治疗的兴起,尤其是分子靶向药物在BTC...     

Biliary tract carcinoma: clinical perspectives on molecular targeting strategies for therapeutic options

Biliary tract carcinoma (BTC) is a lethal malignancy. This lethality is essentially attributed to both slow carcinogenesis occurring under complex pathological circumstances and to the asymptomatic growth of BTC infiltrating the surrounding structures by varying routes. The disease is therefore usually detected at an advanced stage with a high frequency of distant organ metastasis. To date, conventional chemotherapy and radiation therapy have been notably ineffective against BTC. For an improved treatment outcome of BTC and prolonged survival, there is now a real and urgent need to focus on developing novel and potent therapeutic strategies aimed at exploiting select molecular targets associated with tumor proliferation, invasion, and/or metastasis that would impact in a significant way on clinical outcome. The outcomes of recent studies, by the analysis of BTC cells, BTC animal models, and clinical specimens of BTC patients, have revealed, in detail, the molecular mechanism of carcinogenesis and tumor progression of BTC, and these studies have exploited select molecular targets that could significantly impact the clinical outcome. In the near future, the development of new molecular targeting drugs with potent efficacy against BTC, and the performance of randomized clinical trials of these drugs are urgent and essential for the treatment of patients with BTC.     

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.     

Trends and disparities in the utilization of systemic chemotherapy in patients with metastatic hepato-pancreato-biliary cancers

BackgroundWe described trends and disparities in utilization of systemic chemotherapy in metastatic hepato-pancreato-biliary (HPB) cancers.MethodsWe queried the National Cancer Database for metastatic HPB cancers [hepatocellular carcinoma (HCC), biliary tract cancers (BTC), pancreatic adenocarcinoma (PDAC)]. We used multivariable analysis to examine the factors associated with utilization of systemic chemotherapy. We utilized marginal structural logistic models to estimate the effect of health insurance, facility type, or facility volume on utilization of systemic chemotherapy.ResultsWe identified 162,283 patients with metastatic HPB cancers: 23,923 (14.7%) had HCC, 26,766 (16.5%) had BTC, and 111,594 (68.8%) had PDAC.A total of 37.2% patients with HCC, 55.6% with BTC, and 56.4% with PDAC received chemotherapy. Age ≥70 years and Charlson-Deyo score ≥2 were associated with lower likelihood of receiving chemotherapy across all cancers.Patients with private health insurance had higher receipt of chemotherapy. Receiving treatment at academic facilities had no effect on the receipt of chemotherapy. Treatment of patients with HCC or PDAC at high-volume facilities resulted in higher receipt of chemotherapy.ConclusionA significant proportion of patients with metastatic HPB cancers do not receive systemic chemotherapy. Several disparities in administration of chemotherapy for metastatic HPB cancers exist.     

Targeted therapy for biliary tract cancers

Biliary tract cancers (BTCs) are a heterogeneous group of malignancies, with a historically poor prognosis as a whole. Until recently, the development of effective therapeutics was hampered by the relatively low incidence, heterogeneity in patients and tumors, and correspondingly poor clinical trial enrollments. With the publication of the landmark phase III ABC-02 trial demonstrating the superiority of gemcitabine and cisplatin combination chemotherapy, the landscape changed for the development of new agents. Despite this progress, there are currently no approved targeted agents for BTC. This review will focus on recent developments in targeted therapeutics, directed against several key signaling pathways in BTC, including epidermal growth factor receptor, angiogenesis, and the mitogen-activated protein kinase pathway. Data from recent phase I and II trials will be discussed, along with a preview of upcoming trials involving targeted therapies.     

Biological characteristics of cancers in the gallbladder and biliary tract and targeted therapy

Adenocarcinomas of the gallbladder (GBC) and bile ducts (cholangiocarcinoma) (combined as biliary tract cancers, BTC) are uncommon tumors in the United States, but are endemic in parts of South America and Asia. BTC are aggressive tumors with poor survival. Published response rates to chemotherapy are less than 30% and no survival benefit has been demonstrated from palliative systemic therapy. Improved understanding of the biological characteristics and molecular carcinogenic mechanisms of these malignancies may lead to improved therapeutic regimens for patients.     

Biliary tract carcinomas: From chemotherapy to targeted therapy

Biliary tract carcinomas (BTC) are a group of tumours arising from the epithelial cells of intra- and extra-hepatic biliaryducts and the gallbladder, characterised by a poor prognosis.Surgery is the only curative procedure, but the risk of recurrence is high and furthermore, the majority of patients present with unresectable disease at the time of diagnosis. Systemic therapy is the mainstay of treatment for patients who present recurrent or metastatic disease. Progress has been made in the last decade to identify the most effective chemotherapy regimens, with the recent recommendation of the combination of gemcitabine–cisplatin as the standard schedule.Comprehension of the molecular basis of cholangiocarcinogenesis and tumour progression has recently led to the experimentation of targeted therapies in patients with BTC, demonstrating promising results.In this review we will discuss the clinical experience with systemic treatment for BTC, focusing on future directions with targeted therapies.     

Frequent activation of mitogen-activated protein kinase relative to Akt in extrahepatic biliary tract cancer

Background Lack of effective adjuvant therapy against advanced extrahepatic biliary tract carcinoma (BTC) requires that new therapeutic methods, such as molecular targeted therapy, be developed. The mitogen-activated protein kinase (MAPK) and Akt signaling pathways, which activate cell proliferation and suppress apoptosis, respectively, may function as important targets for such therapies. The aim of this study was to examine the expression patterns of phosphorylated MAPK (p-MAPK) and phosphorylated Akt (p-Akt) proteins in BTC cell lines and clinical specimens. Methods Expression of p-MAPK and p-Akt proteins in four human BTC cell lines and in frozen sections of 20 advanced extrahepatic BTC specimens was analyzed by Western blotting. Thirty formalin-fixed BTC specimens were immunohistochemically stained for p-MAPK and p-Akt using labeled streptavidin–biotin conjugates. Results Expression of p-MAPK was observed in three of four (75%) BTC cell lines, whereas no expression of p-Akt was observed. Twenty-three of 30 formalin-fixed specimens stained positive for p-MAPK (77%), whereas only 47% stained positively for p-Akt. Expression of p-MAPK relative to that of p-Akt was also seen more frequently in the frozen specimens. Conclusions The results of this study suggest that MAPK is activated more frequently than Akt in extrahepatic biliary tract carcinoma.     

A successful treatment by hepatic arterial infusion therapy for advanced, unresectable biliary tract cancer

Biliary tract cancers (BTC) are relatively rare tumors, and the prognosis is extremely poor. There has been no standard chemotherapy for advanced BTC. However, recently, gemcitabine (GEM) have been used against BTC as the most active agent, and promising response rates and overall survival times with tolerable drug toxicities have been observed. In this article, two cases of advanced intrahepatic cholangiocarcinoma and unresectable metastatic gallbladder (GB) cancer are reported. They were treated with hepatic arterial infusion (HAI) chemotherapy using a combination of GEM and cisplatin, along with the systemic administration of GEM. As a consequence, multiple liver tumors, the GB cancer and metastatic lymph nodes regressed without severe drug toxicities, and favorable results (the overall survival times were 16 and 14 mo, respectively) were achieved. In conclusion, HAI therapy using GEM combined with cisplatin may be a useful and well-tolerated option for advanced BTC, especially in cases where multiple liver metastases are detected.     

Molecular genetics and targeted therapeutics in biliary tract carcinoma

The primary malignancies of the biliary tract, cholangio-carcinoma and gallbladder cancer, often present at an advanced stage and are marginally sensitive to radiation and chemotherapy. Accumulating evidence indicates that molecularly targeted agents may provide new hope for improving treatment response in biliary tract carcinoma(BTC). In this article, we provide a critical review of the pathogenesis and genetic abnormalities of biliary tract neoplasms, in addition to discussing the current and emerging targeted therapeutics in BTC. Genetic studies of biliary tumors have identified the growth factors and receptors as well as their downstream signaling pathways that control the growth and survival of biliary epithelia. Target-specific monoclonal antibodies and small molecules inhibitors directed against the signaling pathways that drive BTC growth and invasion have been developed. Numerous clinical trials designed to test these agents as either monotherapy or in combination with conventional chemotherapy have been completed or are currently underway. Research focusing on understanding the molecular basis of biliary tumorigenesis will continue to identify for targeted therapy the key mutations that drive growth and invasion of biliary neoplasms. Additional strategies that have emerged for treating this malignant disease include targeting the epigenetic alterations of BTC and immunotherapy. By integrating targeted therapy with molecular profiles of biliary tumor, we hope to provide precision treatment for patients with malignant diseases of the biliary tract.     

Establishment of various biliary tract carcinoma cell lines and xenograft models for appropriate preclinical studies

We recently reported several driver genes of biliary tract carcinoma(BTC) that are known to play important roles in oncogenesis and disease progression. Although the need for developing novel therapeutic strategies is increasing, there are very few BTC cell lines and xenograft models currently available for conducting preclinical studies. Using a total of 88 surgical BTC specimens and 536 immunodeficient mice, 28 xenograft models and 13 new BTC cell lines, including subtypes, were established. Some of our cell lines were found to be resistant to gemcitabine, which is currently the first choice of treatment, thereby allowing highly practical preclinical studies to be conducted. Using the aforementioned cell lines and xenograft models and a clinical pathological database of patients undergoing BTC resection, we can establish a preclinical study system and appropriate parameters for drug efficacy studies to explore new biomarkers for practical applications in the future studies.     

A nationwide analysis of clinical trial participation for common hepato-pancreato-biliary malignancies demonstrates survival advantages for subsets of trial patients but disparities in and infrequency of enrollment

BackgroundWe describe factors associated with trial enrollment for patients with hepato-pancreato-biliary (HPB) malignancies. We analyzed the association and effect of trial enrollment on overall survival (OS).MethodsThe National Cancer Database (2004–2017) was queried for common HPB malignancies (pancreatic adenocarcinoma [PDAC] & neuroendocrine tumors, hepatocellular carcinoma [HCC], biliary tract cancers [BTC]). Multivariable logistic regression was used to identify factors associated with trial enrollment. OS was analyzed by multivariable Cox regression. Inverse-probability-weighted Cox regression was utilized to determine the effect of trial enrollment on OS.ResultsA total of 1573 (0.3%) of 511,639 patients were enrolled in trials; pancreatic malignancy: 1214 (0.4%); HCC: 217 (0.14%); BTC: 106 (0.15%). HCC and BTC were associated with lower likelihood of enrollment compared with pancreatic malignancy. Black and Hispanic patients were less likely to be enrolled compared to White patients. Treatment at academic facilities and metastatic disease were associated with higher likelihood of enrollment. Enrollment was associated with higher OS for PDAC, metastatic HCC, and metastatic BTC. Trial enrollment exhibited an OS advantage for PDAC and metastatic HCC.ConclusionNationally, fewer than 1% of patients with HPB malignancies were enrolled in clinical trials. There are racial, sociodemographic, and facility-based disparities in trial enrollment.     

R0 but not R1/R2 resection is associated with better survival than palliative photodynamic therapy in biliary tract cancer

Background: There is a need for better management strategies to improve the survival and quality of life in patients with biliary tract cancer (BTC). Aim: To assess prognostic factors for survival in a large, non‐selective cohort of patients with BTC. Method: We compared outcomes in 321 patients with a final diagnosis of BTC (cholangiocarcinoma n=237, gallbladder cancer n=84) seen in a tertiary referral cancer centre between 1998 and 2007. Survival according to disease stage and treatment category was compared using log‐rank testing. Cox's regression analysis was used to determine independent prognostic factors. Results: Eighty‐nine (28%) patients underwent a surgical intervention with curative intent, of whom 38% had R0 resections. Among the 321 patients, 34% were given chemo‐ and/or radiotherapy, 14% were palliated with photodynamic therapy (PDT) and 37% with biliary drainage procedures alone. The overall median survival was 9 months (3‐year survival, 14%). R0‐resective surgery conferred the most favourable outcome (3‐year survival, 57%). Although patients palliated with PDT had more advanced clinical T‐stages, their survival was similar to those treated with attempted curative surgery but who had positive resection margins. On multivariable analysis, treatment modality, serum carbohydrate‐associated antigen 19‐9, distant metastases and vascular involvement were independent prognostic indicators of survival. Conclusion: In this large UK series of BTC, palliative PDT resulted in survival similar to those with curatively intended R1/R2 resections. Surgery conferred a survival advantage only in patients with R0 resection margins, emphasising the need for accurate pre‐operative staging.     

Targeting BRCA-mutant biliary tract cancer: Current evidence and future perspectives

Biliary tract cancers (BTCs) are aggressive tumors of the biliary system, which are often diagnosed at the advanced stage with a dismal prognosis. Among BTC patients, germline or somatic breast cancer-related gene 1/2 (BRCA1/2) mutation has been reported and the use of poly(ADP-ribose) polymerase inhibitor (PARPi) has achieved a certain effect, with no obvious severe side effects. The frequencies and mutated types of BRCA1/2 in advanced BTCs vary among studies. BRCA1 and BRCA2 play distinct roles in the development of BTC regardless of age or gender difference. Surprisingly, some BTC patients with germline BRCA mutation can achieve better therapeutic effects than those with a somatic mutation, and patients who carry BRCA mutation are more likely to benefit from immunotherapy alone or in combination. Herein, we provide an overview of the targeted therapies in BRCA-mutant BTCs, with a particular focus on the differences between germline and somatic BRCA1/2 mutations, as well as review the current status and perspectives.     

Systemic treatment options for advanced biliary tract carcinoma

Journal of Gastroenterology - Advanced biliary&nbsp;tract cancers (BTC) include a diverse collection of rare and heterogenous tumors with poor prognosis.&nbsp;The combination of gemcitabine...     

Wisteria floribunda agglutinin-sialylated mucin core polypeptide 1 is a sensitive biomarker for biliary tract carcinoma and intrahepatic cholangiocarcinoma: a multicenter study

Background

Wisteria floribunda agglutinin (WFA)-sialylated mucin core polypeptide 1 (MUC1) was investigated as a new glycoprotein marker for cholangiocarcinoma (CC) using glycoproteomics technologies. In this multicenter study, WFA-sialylated MUC1 levels in serum and bile samples were measured to determine their diagnostic capability in biliary tract carcinoma (BTC) and intrahepatic (Ih) CC.

Methods

The study included 244 patients with BTC, 59 patients with IhCC, 287 patients with benign biliary tract diseases, and 44 control subjects.

Results

Serum WFA-sialylated MUC1 levels were significantly higher in patients with either BTC or IhCC than in control subjects and those with benign biliary tract diseases. Patients with IhCC showed higher WFA-sialylated MUC1 levels than patients with tumors at other sites. No significant differences in WFA-sialylated MUC1 levels were found with regard to cancer stage or tissue type. Receiver operating characteristic curve analysis showed that WFA-sialylated MUC1 was superior to carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) for the diagnosis of benign biliary tract diseases, BTC, and IhCC, as well as for stage I and II carcinomas. Significantly higher levels of biliary WFA-sialylated MUC1 were observed in BTC/IhCC than in benign biliary tract diseases. The diagnostic capability of biliary WFA-sialylated MUC1 was also superior to that of CA19-9, and diagnostic sensitivity was higher than that of biliary cytology for BTC/IhCC.

Conclusions

WFA-sialylated MUC1 is a useful novel biomarker for BTC/IhCC. In the future, this measurement should be applied in the clinical setting.

     

Differential activation of epidermal growth factor (EGF) receptor downstream signaling pathways by betacellulin and EGF

To determine the downstream signaling pathways regulated by betacellulin (BTC) in comparison with epidermal growth factor (EGF), we used Chinese hamster ovary cells overexpressing the human EGF receptor (ErbB1/EGFR). The overall time-dependent activation of EGFR autophosphorylation was identical in cells treated with 1 nm BTC or 1.5 nm EGF. Analysis of site-specific EGFR phosphorylation demonstrated that the BTC and EGF tyrosine phosphorylation of Y1086 was not significantly different. In contrast, the autophosphorylation of Y1173 was markedly reduced in BTC-stimulated cells, compared with EGF stimulation that directly correlated with a reduced BTC stimulation of Shc tyrosine phosphorylation, Ras, and Raf-1 activation. On the other hand, Y1068 phosphorylation was significantly increased after BTC stimulation, compared with EGF in parallel with a greater extent of Erk phosphorylation. Expression of a dominant interfering MEK kinase 1 (MEKK1) and Y1068F EGFR more efficiently blocked the enhanced Erk activation by BTC, compared with EGF. Interestingly BTC had a greater inhibitory effect on apoptosis, compared with EGF, and expression of Y1068F EGFR abolished this enhanced inhibitory effect. Together, these data indicated that although BTC and EGF share overlapping signaling properties, the ability of BTC to enhance Erk activation occurs independent of Ras. The increased BTC activation results from a greater extent of Y1068 EGFR tyrosine phosphorylation and subsequent increased recruitment of the Grb2-MEKK1 complex to the plasma membrane, compared with EGF stimulation. The increased Erk activation by BTC associated with antiapoptotic function.     

Lessons from the comparison of two randomized clinical trials using gemcitabine and cisplatin for advanced biliary tract cancer

There had been no standard chemotherapy established for advanced biliary tract cancer (BTC) until 2009, when the combination of cisplatin and gemcitabine (GC) was adopted as a first line standard chemotherapy option based on the results from two randomized studies: ABC-02, a UK investigator-initiated trial and the largest randomized phase III study in this tumor type with 410 patients; and BT22, a Japanese, industry-sponsored, randomized phase II study with 83 patients. In this review, investigators from both studies collaborated to compare protocols, patient characteristics, and outcomes of both studies including sub-analyses of study results. Although both studies showed GC combination therapy to be more effective than monotherapy, a detailed comparison revealed disparities between efficacy and safety end-points between the studies, which did not necessarily arise from different populations but from differences in protocol design. This review provides clinicians with insights for advanced BTC clinical study design and interpretation of historical studies.