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Purpose: This study aimed to identify the risk factors associated with ampullary duodenal carcinoma (a-DC) and develop a clinical model to dynamically and accurately predict the risk of lymph node metastasis (LNM) in a-DC patients. Methods: Data from 4077 patients (2004–2020) were extracted from the Surveillance, Epidemiology, and End Results database to form a training cohort, while 173 cases (2010–2020) from Zhejiang Provincial People's Hospital in China were used as an external validation cohort. A reliable LASSO-logistic method was employed to identify independent risk factors for a-DC LNM, and a nomogram was developed based on these factors to assess the risk of a-DC LNM. The nomogram was evaluated using the Akaike information criterion, misclassification error, area under the curve, and likelihood ratio test. Finally, the nomogram's accuracy and generalizability were externally validated.. Results: After screening using LASSO and logistic regression four variables were identified as independent risk factors for a-DC LNM: sex (P < 0.001), tumor size (P < 0.001), grade (P < 0.001), and tumor extension (P < 0.001). The area under the curve of the nomogram was 74.8% in the training group and 88.9% in the external validation group. The calibration curves demonstrated that the LNM predictions made by the nomogram were in satisfactory agreement with the actual observed LNM. Additionally, the decision curve analysis curves indicated effective clinical utility of the nomogram. Conclusions: A nomogram based on the LASSO-logistic analysis was constructed to predict a-DC LNM, demonstrating good performance and clinical application value. [ABSTRACT FROM AUTHOR]

Abstract Background Despite the recent advances in cancer treatment, the therapeutic options for patients with biliary tract cancer are still very limited and the prognosis very poor. More than 50% of newly diagnosed patients with biliary tract cancer are not amenable to curative surgical treatment and thus treated with palliative systemic treatment. Malignant bile duct obstructions in patients with perihilar and/or ductal cholangiocarcinoma (CCA) represents one of the most important challenges in the management of these patients, owning to the risk represented by developing life-threatening cholangitis which, in turn, limits the use of systemic treatment. For this reason, endoscopic stenting and/or bile duct decompression is the mainstay of treatment of these patients. Data on efficacy and safety of adding radiofrequency ablation (RFA) to biliary stenting is not conclusive. The aim of this multicenter, randomized trial is to evaluate the effect of intraductal RFA prior to bile duct stenting in patients with unresectable perihilar or ductal CCA undergoing palliative systemic therapy. Methods/Design ACTICCA-2 is a multicenter, randomized, controlled, open-label, investigator-initiated trial. 120 patients with perihilar or ductal CCA with indication for biliary stenting and systemic therapy will be randomized 1:1 to receive either RFA plus bile duct stenting (interventional arm) or bile duct stenting alone (control arm). Patients will be stratified by trial site and tumor location (perihilar vs. ductal). Both arms receive palliative systemic treatment according to the local standard of care determined by a multidisciplinary tumorboard. The primary endpoint is time to first biliary event, which is determined by an increase of bilirubin to > 5 mg/dl and/or the occurrence of cholangitis leading to premature stent replacement and/or disruption of chemotherapy. Secondary endpoints include overall survival, safety according to NCI CTCAE v5, quality of life assessed by questionnaires (EORTC QLQ-C30 and QLQ-BIL21), clinical event rate at 6 months after RFA and total days of over-night stays in hospital. Follow-up for the primary endpoint will be 6 months, while survival assessment will be continued until end of study (maximum follow-up 30 month). All patients who are randomized and who underwent endoscopic stenting will be used for the primary endpoint analysis which will be conducted using a cause-specific Cox proportional hazards model with a frailty for trial site and fixed effects for the treatment group, tumor location, and stent material. Discussion ACTICCA-2 is a multicenter, randomized, controlled trial to assess efficacy and safety of adding biliary RFA to bile duct stenting in patients with CCA receiving palliative systemic treatment. Trial registration The study is registered with ClinicalTrials.gov (NCT06175845) and approved by the local ethics committee in Hamburg, Germany (2024-101232-BO-ff). This manuscript reflects protocol version 1 as of January 9th, 2024. Graphical Abstract

Background: Despite the recent advances in cancer treatment, the therapeutic options for patients with biliary tract cancer are still very limited and the prognosis very poor. More than 50% of newly diagnosed patients with biliary tract cancer are not amenable to curative surgical treatment and thus treated with palliative systemic treatment. Malignant bile duct obstructions in patients with perihilar and/or ductal cholangiocarcinoma (CCA) represents one of the most important challenges in the management of these patients, owning to the risk represented by developing life-threatening cholangitis which, in turn, limits the use of systemic treatment. For this reason, endoscopic stenting and/or bile duct decompression is the mainstay of treatment of these patients. Data on efficacy and safety of adding radiofrequency ablation (RFA) to biliary stenting is not conclusive. The aim of this multicenter, randomized trial is to evaluate the effect of intraductal RFA prior to bile duct stenting in patients with unresectable perihilar or ductal CCA undergoing palliative systemic therapy. Methods/Design: ACTICCA-2 is a multicenter, randomized, controlled, open-label, investigator-initiated trial. 120 patients with perihilar or ductal CCA with indication for biliary stenting and systemic therapy will be randomized 1:1 to receive either RFA plus bile duct stenting (interventional arm) or bile duct stenting alone (control arm). Patients will be stratified by trial site and tumor location (perihilar vs. ductal). Both arms receive palliative systemic treatment according to the local standard of care determined by a multidisciplinary tumorboard. The primary endpoint is time to first biliary event, which is determined by an increase of bilirubin to > 5 mg/dl and/or the occurrence of cholangitis leading to premature stent replacement and/or disruption of chemotherapy. Secondary endpoints include overall survival, safety according to NCI CTCAE v5, quality of life assessed by questionnaires (EORTC QLQ-C30 and QLQ-BIL21), clinical event rate at 6 months after RFA and total days of over-night stays in hospital. Follow-up for the primary endpoint will be 6 months, while survival assessment will be continued until end of study (maximum follow-up 30 month). All patients who are randomized and who underwent endoscopic stenting will be used for the primary endpoint analysis which will be conducted using a cause-specific Cox proportional hazards model with a frailty for trial site and fixed effects for the treatment group, tumor location, and stent material. Discussion: ACTICCA-2 is a multicenter, randomized, controlled trial to assess efficacy and safety of adding biliary RFA to bile duct stenting in patients with CCA receiving palliative systemic treatment. Trial registration: The study is registered with ClinicalTrials.gov (NCT06175845) and approved by the local ethics committee in Hamburg, Germany (2024-101232-BO-ff). This manuscript reflects protocol version 1 as of January 9th, 2024. [ABSTRACT FROM AUTHOR]

Abstract Background Biliary tract cancer (BTC) is a relatively rare but aggressive gastrointestinal cancer with a high mortality rate. Cancer stem cell (CSC) populations play crucial roles in tumor biology and are responsible for the low response to anti-cancer treatment and the high recurrence rate. This study investigated the role of Transgelin-2 (TAGLN2), overexpressed in CSC in BTC cells, and analyzed its expression in patient tissues and serum to identify potential new targets for BTC. Methods TAGLN2 expression was suppressed by small-interfering or short hairpin RNAs, and its effects on tumor biology were assessed in several BTC cell lines. Furthermore, the effects of TAGLN2 silencing on gemcitabine-resistant BTC cells, differentially expressed genes, proteins, and sensitivity to therapeutics or radiation were assessed. TAGLN2 expression was also assessed using western blotting and immunohistochemistry in samples obtained from patients with BTC to validate its clinical application. Results Suppression of TAGLN2 in BTC cell lines decreased cell proliferation, migration, invasion, and tumor size, in addition to a reduction in CSC features, including clonogenicity, radioresistance, and chemoresistance. TAGLN2 was highly expressed in BTC tissues, especially in cancer-associated fibroblasts in the stroma. Patients with a low stromal immunohistochemical index had prolonged disease-free survival compared to those with a high stromal immunohistochemical index (11.5 vs. 7.4 months, P = 0.013). TAGLN2 expression was higher in the plasma of patients with BTC than that in those with benign diseases. TAGLN2 had a higher area under the curve (0.901) than CA19-9, a validated tumor biomarker (0.799; P

Objective: To screen the risk factors affecting the recurrence risk of patients with ampullary carcinoma (AC)after radical resection, and then to construct a model for risk prediction based on Lasso-Cox regression and visualize it. Methods: Clinical data were collected from 162 patients that received pancreaticoduodenectomy treatment in Hebei Provincial Cancer Hospital from January 2011 to January 2022. Lasso regression was used in the training group to screen the risk factors for recurrence. The Lasso-Cox regression and Random Survival Forest (RSF) models were compared using Delong test to determine the optimum model based on the risk factors. Finally, the selected model was validated using clinical data from the validation group. Results: The patients were split into two groups, with a 7:3 ratio for training and validation. The variables screened by Lasso regression, such as CA19-9/GGT, AJCC 8th edition TNM staging, Lymph node invasion, Differentiation, Tumor size, CA19-9, Gender, GPR, PLR, Drinking history, and Complications, were used in modeling with the Lasso-Cox regression model (C-index = 0.845) and RSF model (C-index = 0.719) in the training group. According to the Delong test we chose the Lasso-Cox regression model (P = 0.019) and validated its performance with time-dependent receiver operating characteristics curves(tdROC), calibration curves, and decision curve analysis (DCA). The areas under the tdROC curves for 1, 3, and 5 years were 0.855, 0.888, and 0.924 in the training group and 0.841, 0.871, and 0.901 in the validation group, respectively. The calibration curves performed well, as well as the DCA showed higher net returns and a broader range of threshold probabilities using the predictive model. A nomogram visualization is used to display the results of the selected model. Conclusion: The study established a nomogram based on the Lasso-Cox regression model for predicting recurrence in AC patients. Compared to a nomogram built via other methods, this one is more robust and accurate. [ABSTRACT FROM AUTHOR]

Abstract Background Biliary tract cancer (BTC) is a relatively rare but highly aggressive malignancy. However, there is currently no satisfactory second-line regimen for patients without specific genetic mutations. Nanoparticle albumin–bound paclitaxel, also known as nab-paclitaxel (Abraxane, Bristol Myers Squibb), has shown activity in patients with BTC. Studies investigating the immunogenic features of BTC suggested that checkpoint inhibition may lead to antitumor immune responses. In recent years, improved survival has been observed in patients treated with chemotherapy combined with immunotherapy across multiple cancer types, including BTC. This clinical trial aims to evaluate the efficacy and safety of second-line sintilimab in combination with nab-paclitaxel in advanced BTC patients. Methods The NapaSinti trial is a prospective, nonrandomized, open-label, phase 2 study conducted at a tertiary hospital in Chengdu, China. Eligible patients are those with histologically or cytologically confirmed locally advanced non-resectable or metastatic adenocarcinoma in the biliary tract (including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer), aged between 18 and 75 years, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, who have experienced disease progression after prior gemcitabine- or fluorouracil-based chemotherapy and have not received taxane or immune checkpoint inhibitor treatment. Enrolled patients will receive intravenous administration of sintilimab 200 mg on day 1 and nab-paclitaxel 125 mg/m2 on days 1 and 8, every three weeks. The primary endpoint is the objective response rate (ORR), while the secondary endpoints include overall survival (OS), progression-free survival (PFS), and safety. Exploratory objectives aim to identify biomarkers and molecular signatures for predicting response or prognosis. Using Simon’s two-stage design, a total of 63 participants will be enrolled in the study. This trial was initiated in March 2022 in China. Discussion The NapaSinti trial evaluates the efficacy and safety of second-line sintilimab plus nab-paclitaxel for advanced biliary tract cancer. Additionally, the trial provides an opportunity for translational research. Trial registration Chinese Clinical Trial Registry ChiCTR2100052118. Registered October 19, 2021.

Objective: The objective of this study is to evaluate the cost-effectiveness of adding pembrolizumab to the standard first-line therapy of advanced biliary tract cancer (BTC) with gemcitabine and cisplatin from the perspective of the Chinese healthcare system. Methods: The partitioned survival model developed from clinical data obtained in The KEYNOTE-966 trial served as the basis for a simulation in the TreeAge Pro 2011 software. The objective of the research was to estimate the 10-year life expectancy and total healthcare costs of patients with BTC, utilizing primary outcomes that evaluated costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER). To establish the willingness-to-pay (WTP) threshold, the 2022 Chinese per capita gross domestic product (GDP) of $37304.346/QALY was adopted. Furthermore, sensitivity analysis was conducted to ascertain the study's results under varying levels of uncertainty. Results: Compared to chemotherapy alone, the addition of pembrolizumab to chemotherapy has been shown to yield an incremental gain of 0.184 quality-adjusted life years (QALY) at an additional cost of $103940.706. This translates into an incremental cost-effectiveness ratio (ICER) of $564895.141/QALY, which exceeds the willingness-to-pay (WTP) threshold in China. One-way sensitivity analyses performed on the model recognize the utility of PD, subsequent cost, and the cost of Pembrolizumab 100 mg had a major influence on the outcomes. However, no parameter elicited an ICER lower than the willingness-to-pay (WTP) threshold. Conclusions: Based on the perspective of the Chinese healthcare system, the utilization of pembrolizumab in combination with chemotherapy as an first-line treatment option for BTC does not appear to be a cost-effective approach compared to chemotherapy as a standalone therapy. [ABSTRACT FROM AUTHOR]

Abstract Background The prognosis of patients with advanced biliary tract cancer (BTC) who have progressed on gemcitabine plus cisplatin is dismal. Trifluridine/tipiracil (FTD/TPI) and irinotecan have proven efficacy in different gastrointestinal malignancies. We therefore hypothesized that this combination might improve the therapeutic outcome in patients with BTC after failure of first line treatment. Methods TRITICC is an interventional, prospective, open-label, non-randomised, exploratory, multicentre, single-arm phase IIA clinical trial done in 6 sites with expertise in managing biliary tract cancer across Germany. A total of 28 adult patients (aged ≥ 18 years) with histologically verified locally advanced or metastatic biliary tract cancer (including cholangiocarcinoma and gallbladder or ampullary carcinoma) with documented radiological disease progression to first-line gemcitabine based chemotherapy will be included to receive a combination of FTD/TPI plus irinotecan according to previously published protocols. Study treatment will be continued until disease progression according to RECIST 1.1 criteria or occurrence of unacceptable toxicity. The effect of FTD/TPI plus irinotecan on progression-free survival will be analyzed as primary endpoint. Safety (according to NCI-CTCAE), response rates and overall survival are secondary endpoints. In addition, a comprehensive translational research program is part of the study and might provide findings about predictive markers with regard to response, survival periods and resistance to treatment. Discussion The aim of TRITICC is to evaluate the safety and efficacy of FTD/TPI plus irinotecan in patients with biliary tract cancer refractory to previous Gemcitabine based treatment. Trial registration EudraCT 2018–002936-26; NCT04059562

Abstract Background Malignant tumors of the biliary system are characterized by a high degree of malignancy and strong invasiveness, and they are usually diagnosed at late stages with poor prognosis. For patients with advanced biliary tract cancer, chemotherapy and targeted therapy are two of the options available to improve prognosis and delay tumor progression. This study aimed to comprehensively evaluate the safety and effectiveness of various chemotherapy schemes for the treatment of advanced biliary tract cancer in published systematic reviews and meta-analyses (SRoMAs). Methods An umbrella review method was adopted, which aims to summarize the existing evidence from multiple studies around a research topic. SRoMAs up to April 9, 2022, were identified using PubMed, Web of Science, the Cochrane database, and manual screening. Eligible studies were screened according to inclusion and exclusion criteria. This study had been registered at PROSPERO (CRD42022324548). For each eligible study, we extracted the data of general characteristics and the main findings. The methodological quality of the included studies were assessed by the AMSTAR2 scale, and the quality of evidence was evaluated by the GRADE tools. Results A total of 1833 articles were searched; 14 unique articles with 94 outcomes were identified by eligibility criteria. The incidence of skin rash (RR = 18.11, 95% CI 5.13–63.91, GRADE: Moderate) and diarrhea (RR = 2.48, 95% CI 1.2–5.10, GRADE: Moderate) was higher in patients receiving gemcitabine-based chemotherapy plus targeted therapy than in patients receiving gemcitabine monotherapy. The number of patients receiving gemcitabine-based chemotherapy who developed leukopenia (OR = 7.17, 95% CI 1.43–36.08, GRADE: Moderate), anemia (OR = 7.04, 95% CI 2.59–19.12, GRADE: High), thrombocytopenia (RR = 2.45, 95% CI 1.39–4.32, GRADE: Moderate), and neutropenia (RR = 3.30, 95% CI 1.04–10.50, GRADE: Moderate) was significantly higher than that of patients who received gemcitabine-free regimens. In addition, patients receiving S-1 monotherapy had significantly better ORR (RR = 2.46, 95% CI 1.27–4.57, GRADE: Moderate) than patients receiving S-1 + gemcitabine. Patients receiving fluoropyrimidine-based chemotherapy had longer OS (HR = 0.83, 95% CI 0.7–0.99, GRADE: Moderate), higher DCR (0R = 5.18, 95% CI 3.3–10.23, GRADE: Moderate), and higher ORR (0R = 3.24, 95% CI 1.18–8.92, GRADE: Moderate) compared with patients who received 5-FU/LV monotherapy or supportive therapy. Surprisingly, we found evidence that gemcitabine-based chemotherapy did not improve postoperative patients’ OS (HR = 0.91, 95% CI 0.74–1.12, GRADE: Moderate) when compared with best supportive care. Conclusions This study comprehensively evaluated the safety and efficacy of chemotherapy or targeted therapy regimens for advanced biliary tract cancer and found 11 outcomes with “Moderate” or “High” levels; however, most of the outcomes were still at “low” or “very low” levels. More randomized controlled studies are needed in the future to further summarize high levels of evidence.

Background: Biliary tract cancer (BTC) is a relatively rare but highly aggressive malignancy. However, there is currently no satisfactory second-line regimen for patients without specific genetic mutations. Nanoparticle albumin–bound paclitaxel, also known as nab-paclitaxel (Abraxane, Bristol Myers Squibb), has shown activity in patients with BTC. Studies investigating the immunogenic features of BTC suggested that checkpoint inhibition may lead to antitumor immune responses. In recent years, improved survival has been observed in patients treated with chemotherapy combined with immunotherapy across multiple cancer types, including BTC. This clinical trial aims to evaluate the efficacy and safety of second-line sintilimab in combination with nab-paclitaxel in advanced BTC patients. Methods: The NapaSinti trial is a prospective, nonrandomized, open-label, phase 2 study conducted at a tertiary hospital in Chengdu, China. Eligible patients are those with histologically or cytologically confirmed locally advanced non-resectable or metastatic adenocarcinoma in the biliary tract (including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer), aged between 18 and 75 years, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, who have experienced disease progression after prior gemcitabine- or fluorouracil-based chemotherapy and have not received taxane or immune checkpoint inhibitor treatment. Enrolled patients will receive intravenous administration of sintilimab 200 mg on day 1 and nab-paclitaxel 125 mg/m2 on days 1 and 8, every three weeks. The primary endpoint is the objective response rate (ORR), while the secondary endpoints include overall survival (OS), progression-free survival (PFS), and safety. Exploratory objectives aim to identify biomarkers and molecular signatures for predicting response or prognosis. Using Simon's two-stage design, a total of 63 participants will be enrolled in the study. This trial was initiated in March 2022 in China. Discussion: The NapaSinti trial evaluates the efficacy and safety of second-line sintilimab plus nab-paclitaxel for advanced biliary tract cancer. Additionally, the trial provides an opportunity for translational research. Trial registration: Chinese Clinical Trial Registry ChiCTR2100052118. Registered October 19, 2021. [ABSTRACT FROM AUTHOR]

Abstract Background Intrahepatic cholangiocarcinoma (CCA) is amongst the most common primary liver tumors worldwide. CCA carries a bad prognosis prompting research to establish new treatment modalities other than surgery and the current chemotherapeutic regimens adopted. Hence, this trial explores a new therapeutic approach, to combine stereotactic body radiation therapy (SBRT) and immunotherapy (Nivolumab), and asses its clinical benefit and safety profile after induction chemotherapy in CCA. Methodology This is a Phase II open-label, single-arm, multicenter study that investigates Nivolumab (PD-1 inhibitor) treatment at Day 1 followed by SBRT (30 Gy in 3 to 5 fractions) at Day 8, then monthly Nivolumab in 40 patients with non-resectable locally advanced, metastatic or recurrent intrahepatic or extrahepatic CCA. Eligible patients were those above 18 years of age with a pathologically and radiologically confirmed diagnosis of non-resectable locally advanced or metastatic or recurrent intrahepatic or extrahepatic CCA, following 4 cycles of cisplatin-based chemotherapy with an estimated life expectancy of more than 3 months, among other criteria. The primary endpoint is the progression free survival (PFS) rate at 8 months and disease control rate (DCR). The secondary endpoints are overall survival (OS), tumor response rate (TRR), duration of response, evaluation of biomarkers: CD3 + , CD4 + and CD8 + T cell infiltration, as well as any change in the PD-L1 expression through percutaneous core biopsy when compared with the baseline biopsy following 1 cycle of Nivolumab and SBRT. Discussion SRBT alone showed promising results in the literature by both inducing the immune system locally and having abscopal effects on distant metastases. Moreover, given the prevalence of PD-L1 in solid tumors, targeting it or its receptor has become the mainstay of novel immunotherapeutic drugs use. A combination of both has never been explored in the scope of CCA and that is the aim of this study. Trial registration ClinicalTrials.gov NCT04648319 , April 20, 2018.

Abstract Background Biliary tract cancer (BTC) includes intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma, gallbladder cancer, and ampulla of Vater cancer (AVC). Although BTC is rare in the US, incidence is increasing and elevated in certain populations. This study examined BTC epidemiology in the US by age, sex, race/ethnicity, geographic region, and anatomic site. Methods BTC incidence, prevalence, mortality, and survival from 2001 to 2015 were evaluated using the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program and the Centers for Disease Control and Prevention’s National Program of Cancer Registries databases. Incidence and mortality rates were calculated and reported as age-standardized rates. Data were assessed by age, anatomic sites, geographic region, and race/ethnicity, and a joinpoint regression model was used to predict trends for age-adjusted BTC incidence and mortality rates. Results BTC incidence increased during the study period (annual percent change = 1.76, 95% confidence interval [1.59–1.92]), with the highest increase in ICC (6.65 [6.11–7.19]). Incidence of unspecified BTC initially increased but has recently begun to drop. Hispanic, Asian/Pacific Islander, Black, or American Indian/Alaska Native race/ethnicity was associated with higher BTC mortality rates than White race/ethnicity. Patients with ICC had the highest mortality rate (age-standardized rate = 1.87/100,000 person-years [1.85–1.88]). Five-year survival was 15.2% for all BTC, ranging from 8.5% (ICC) to 34.5% (AVC), and patients with distant disease at diagnosis had lower survival (3%) compared with those with regional (19.1%) or locally advanced disease (31.5%). Conclusions BTC incidence increased, survival was low across all subtypes, and mortality was greatest in patients with ICC. This underscores the serious, increasing unmet need among patients with BTC. Treatment options are limited, although clinical studies investigating immunotherapy, targeted therapies, and alternative chemotherapy combinations are ongoing. Epidemiological insights may improve patient care and inform the integration of novel therapies for BTC.

Background: The prognosis of patients with advanced biliary tract cancer (BTC) who have progressed on gemcitabine plus cisplatin is dismal. Trifluridine/tipiracil (FTD/TPI) and irinotecan have proven efficacy in different gastrointestinal malignancies. We therefore hypothesized that this combination might improve the therapeutic outcome in patients with BTC after failure of first line treatment. Methods: TRITICC is an interventional, prospective, open-label, non-randomised, exploratory, multicentre, single-arm phase IIA clinical trial done in 6 sites with expertise in managing biliary tract cancer across Germany. A total of 28 adult patients (aged ≥ 18 years) with histologically verified locally advanced or metastatic biliary tract cancer (including cholangiocarcinoma and gallbladder or ampullary carcinoma) with documented radiological disease progression to first-line gemcitabine based chemotherapy will be included to receive a combination of FTD/TPI plus irinotecan according to previously published protocols. Study treatment will be continued until disease progression according to RECIST 1.1 criteria or occurrence of unacceptable toxicity. The effect of FTD/TPI plus irinotecan on progression-free survival will be analyzed as primary endpoint. Safety (according to NCI-CTCAE), response rates and overall survival are secondary endpoints. In addition, a comprehensive translational research program is part of the study and might provide findings about predictive markers with regard to response, survival periods and resistance to treatment. Discussion: The aim of TRITICC is to evaluate the safety and efficacy of FTD/TPI plus irinotecan in patients with biliary tract cancer refractory to previous Gemcitabine based treatment. Trial registration: EudraCT 2018–002936-26; NCT04059562 [ABSTRACT FROM AUTHOR]

Background: Intrahepatic cholangiocarcinoma (CCA) is amongst the most common primary liver tumors worldwide. CCA carries a bad prognosis prompting research to establish new treatment modalities other than surgery and the current chemotherapeutic regimens adopted. Hence, this trial explores a new therapeutic approach, to combine stereotactic body radiation therapy (SBRT) and immunotherapy (Nivolumab), and asses its clinical benefit and safety profile after induction chemotherapy in CCA. Methodology: This is a Phase II open-label, single-arm, multicenter study that investigates Nivolumab (PD-1 inhibitor) treatment at Day 1 followed by SBRT (30 Gy in 3 to 5 fractions) at Day 8, then monthly Nivolumab in 40 patients with non-resectable locally advanced, metastatic or recurrent intrahepatic or extrahepatic CCA. Eligible patients were those above 18 years of age with a pathologically and radiologically confirmed diagnosis of non-resectable locally advanced or metastatic or recurrent intrahepatic or extrahepatic CCA, following 4 cycles of cisplatin-based chemotherapy with an estimated life expectancy of more than 3 months, among other criteria. The primary endpoint is the progression free survival (PFS) rate at 8 months and disease control rate (DCR). The secondary endpoints are overall survival (OS), tumor response rate (TRR), duration of response, evaluation of biomarkers: CD3 + , CD4 + and CD8 + T cell infiltration, as well as any change in the PD-L1 expression through percutaneous core biopsy when compared with the baseline biopsy following 1 cycle of Nivolumab and SBRT. Discussion: SRBT alone showed promising results in the literature by both inducing the immune system locally and having abscopal effects on distant metastases. Moreover, given the prevalence of PD-L1 in solid tumors, targeting it or its receptor has become the mainstay of novel immunotherapeutic drugs use. A combination of both has never been explored in the scope of CCA and that is the aim of this study. Trial registration: ClinicalTrials.gov NCT04648319, April 20, 2018. [ABSTRACT FROM AUTHOR]

Background: Biliary tract cancer (BTC) includes intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma, gallbladder cancer, and ampulla of Vater cancer (AVC). Although BTC is rare in the US, incidence is increasing and elevated in certain populations. This study examined BTC epidemiology in the US by age, sex, race/ethnicity, geographic region, and anatomic site. Methods: BTC incidence, prevalence, mortality, and survival from 2001 to 2015 were evaluated using the National Cancer Institute's Surveillance, Epidemiology, and End Results Program and the Centers for Disease Control and Prevention's National Program of Cancer Registries databases. Incidence and mortality rates were calculated and reported as age-standardized rates. Data were assessed by age, anatomic sites, geographic region, and race/ethnicity, and a joinpoint regression model was used to predict trends for age-adjusted BTC incidence and mortality rates. Results: BTC incidence increased during the study period (annual percent change = 1.76, 95% confidence interval [1.59–1.92]), with the highest increase in ICC (6.65 [6.11–7.19]). Incidence of unspecified BTC initially increased but has recently begun to drop. Hispanic, Asian/Pacific Islander, Black, or American Indian/Alaska Native race/ethnicity was associated with higher BTC mortality rates than White race/ethnicity. Patients with ICC had the highest mortality rate (age-standardized rate = 1.87/100,000 person-years [1.85–1.88]). Five-year survival was 15.2% for all BTC, ranging from 8.5% (ICC) to 34.5% (AVC), and patients with distant disease at diagnosis had lower survival (3%) compared with those with regional (19.1%) or locally advanced disease (31.5%). Conclusions: BTC incidence increased, survival was low across all subtypes, and mortality was greatest in patients with ICC. This underscores the serious, increasing unmet need among patients with BTC. Treatment options are limited, although clinical studies investigating immunotherapy, targeted therapies, and alternative chemotherapy combinations are ongoing. Epidemiological insights may improve patient care and inform the integration of novel therapies for BTC. [ABSTRACT FROM AUTHOR]

Abstract Background Associations of High-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, total cholesterol (CHL), and triglyceride (TRG) concentrations with risk of biliary tract cancer (BtC) were conflicting in observational studies. We aim to investigate the causal link between circulating lipids and BtC using genetic information. Methods Single nucleotide polymorphisms of the four circulating lipids (n = 34,421) and BtC (418 cases and 159,201 controls) were retrieved from two independent GWAS studies performed in East Asian populations. Two-sample univariate and multivariate Mendelian Randomization (MR) analyses were conducted to determine the causal link between circulating lipids and BtC. Results No significant horizontal pleiotropy was detected for all circulating lipids according to the MR-PRESSO global test (P = 0.458, 0.368, 0.522, and 0.587 for HDL, LDL, CHL, and TRG, respectively). No significant evidence of heterogeneity and directional pleiotropy was detected by the Cochran’s Q test and MR-Egger regression. Univariate MR estimates from inverse variance weighting method suggested that one standard deviation (1-SD) increase of inverse-normal transformed HDL (OR = 1.38, 95% CI 0.98–1.94), LDL (OR = 1.46, 95% CI 0.96–2.23), and CHL (OR = 1.34, 95% CI 0.83–2.16) were not significantly associated with BtC risk. Whereas 1-SD increase of inverse-normal transformed TRG showed a significantly negative association with BtC risk (OR = 0.48, 95% CI 0.31–0.74). In multivariate MR analyses including all the four lipid traits, we found that 1-SD increase of LDL and TRG was significantly associated with elevated (OR = 1.32, 95% CI 1.04–2.01) and decreased (OR = 0.54, 95% CI 0.42–0.68) risk of BtC, respectively. Conclusion Circulating lipids, particularly LDL and TRG, may have roles in the development of BtC. However, the results of this study should be replicated in MR with larger GWAS sample sizes for BtC.

Abstract Background Annexin A10 expression influences the prognosis of several gastrointestinal cancers. We explored the association of annexin A10 expression with the overall survival (OS) of patients who underwent curative surgery for cholangiocarcinoma. Methods Patients who underwent curative surgery for cholangiocarcinoma (except gallbladder cancer) and had pathological stage T1-3N0M0 disease were enrolled. Annexin A10 expression was examined by performing immunohistochemical staining. Patient demographics and survival outcome data were retrieved from medical records. Results In total, 185 patients were enrolled. The primary tumor location was intrahepatic and extrahepatic (including the perihilar region) for 89% and 11% of patients, respectively. Positive annexin A10 staining was detected for 61 (33%) patients and associated with extrahepatic or perihilar cholangiocarcinoma (p = 0.001) and lower histological grade (p

This document is a correction notice for an article published in BMC Cancer. The authors reported an error in the funding section of their article and provided the correct funding statement. The study is an investigator-driven trial sponsored by Gruppo Oncologico del Nord Ovest and funded by GONO Foundation, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, and Fondazione Anna Villa e Felice Rusconi Onlus. The project is also in collaboration with Intesa Sanpaolo S.p.A. The study will be conducted according to current regulations. Springer Nature, the publisher, remains neutral with regard to jurisdictional claims and institutional affiliations. [Extracted from the article]

Background: Associations of High-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, total cholesterol (CHL), and triglyceride (TRG) concentrations with risk of biliary tract cancer (BtC) were conflicting in observational studies. We aim to investigate the causal link between circulating lipids and BtC using genetic information.Methods: Single nucleotide polymorphisms of the four circulating lipids (n = 34,421) and BtC (418 cases and 159,201 controls) were retrieved from two independent GWAS studies performed in East Asian populations. Two-sample univariate and multivariate Mendelian Randomization (MR) analyses were conducted to determine the causal link between circulating lipids and BtC.Results: No significant horizontal pleiotropy was detected for all circulating lipids according to the MR-PRESSO global test (P = 0.458, 0.368, 0.522, and 0.587 for HDL, LDL, CHL, and TRG, respectively). No significant evidence of heterogeneity and directional pleiotropy was detected by the Cochran's Q test and MR-Egger regression. Univariate MR estimates from inverse variance weighting method suggested that one standard deviation (1-SD) increase of inverse-normal transformed HDL (OR = 1.38, 95% CI 0.98-1.94), LDL (OR = 1.46, 95% CI 0.96-2.23), and CHL (OR = 1.34, 95% CI 0.83-2.16) were not significantly associated with BtC risk. Whereas 1-SD increase of inverse-normal transformed TRG showed a significantly negative association with BtC risk (OR = 0.48, 95% CI 0.31-0.74). In multivariate MR analyses including all the four lipid traits, we found that 1-SD increase of LDL and TRG was significantly associated with elevated (OR = 1.32, 95% CI 1.04-2.01) and decreased (OR = 0.54, 95% CI 0.42-0.68) risk of BtC, respectively.Conclusion: Circulating lipids, particularly LDL and TRG, may have roles in the development of BtC. However, the results of this study should be replicated in MR with larger GWAS sample sizes for BtC. [ABSTRACT FROM AUTHOR]

Abstract Introduction The present study aims to evaluate the efficacy and safety of apatinib monotherapy or combination therapy for patients with advanced or recurrent biliary tract cancer (BTC). Methods Twenty-eight patients with advanced or recurrent BTC who progressed after prior systemic therapies and treated with apatinib from January 2017 to June 2019 were enrolled in this retrospective and observational study. The primary end point was progression free survival (PFS). Secondary end points included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and toxicity. Results A total of 28 patients with advanced or recurrent BTC who progressed after prior systemic therapies received apatinib monotherapy or combination therapy (with capecitabine, S-1, oxaliplatin, irinotecan or PD-1 inhibitor), including 9 cases of gallbladder cancer and 19 cases of cholangiocarcinoma. Six patients achieved PR, 15 patients had SD and 7 patients had PD. Median progression-free survival (PFS) and overall survival (OS) was 4.3 months (95%CI = 1.8–6.8) and 6.2 months (95% CI = 4.6–7.8) respectively. The ORR and DCR were 21.4% (6/28) and 75.0% (21/28), respectively. Most of the adverse events were grade 1–2 in severity, apatinib treatment was well tolerated. Conclusions Apatinib monotherapy or combination therapy can improve PFS in patients with advanced or recurrent BTC who progressed after prior systemic therapies, and adverse reactions can be well tolerated. Our study support apatinib therapy as a feasible therapeutic strategy in advanced or recurrent BTC.

Abstract Background Biliary tract cancer (BTC) has a poor prognosis and lacks a standardized second-line therapy. Vascular endothelial growth factor (VEGF), fibroblast growth factor receptor (FGFR) 4, and platelet-derived growth factor receptor (PDGFR) are highly expressed in BTC. Therefore, lenvatinib (a known inhibitor of VEGF receptors 1–3, FGFRs 1–4, and PDGFR-α) was evaluated for second-line treatment of BTC. Methods In this single-arm, multicenter, open-label, phase 2 study, patients with BTC received lenvatinib 24 mg orally once daily in 28-day cycles. The primary endpoint was objective response rate (ORR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), PFS rate at 12 weeks, disease control rate, clinical benefit rate, safety and pharmacokinetic profiles. Results Twenty-six Japanese patients were enrolled and treated; 3 had a confirmed partial response per investigator assessment and per independent imaging review (IIR); ORR was 11.5% (90% confidence interval [CI]: 3.2–27.2). Median PFS was 3.19 months (95% CI: 2.79–7.23) per investigator assessment and 1.64 months (95% CI: 1.41–3.19) per IIR. Median OS was 7.35 months (95% CI: 4.50–11.27). Grade ≥ 3 treatment-emergent adverse events (TEAEs) occurred in 21 patients (80.8%) and included hypertension (n = 10 [38.5%]), proteinuria (n = 3 [11.5%]), palmar-plantar erythrodysesthesia (n = 3 [11.5%]), decreased appetite (n = 3 [11.5%]), and anemia (n = 3 [11.5%]). Two deaths occurred due to TEAEs between treatment initiation and 30 days after last dose, but neither were considered treatment related. Conclusions Lenvatinib demonstrated antitumor activity in BTC, with a tolerable safety profile, and should be further evaluated as potential second-line therapy for this difficult to treat population. Trial registration ClinicalTrials.gov NCT02579616 . Date of registration: October 19, 2015.

Abstract Background Although surgery is the definitive curative treatment for biliary tract cancer (BTC), outcomes after surgery alone have not been satisfactory. Adjuvant therapy with S-1 may improve survival in patients with BTC. This study examined the safety and efficacy of 1 year adjuvant S-1 therapy for BTC in a multi-institutional trial. Methods The inclusion criteria were as follows: histologically proven BTC, Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, R0 or R1 surgery performed, cancer classified as Stage IB to III. Within 10 weeks post-surgery, a 42-day cycle of treatment with S-1 (80 mg/m2/day orally twice daily on days 1–28 of each cycle) was initiated and continued up to 1 year post surgery. The primary endpoint was adjuvant therapy completion rate. The secondary endpoints were toxicities, disease-free survival (DFS), and overall survival (OS). Results Forty-six patients met the inclusion criteria of whom 19 had extrahepatic cholangiocarcinoma, 10 had gallbladder carcinoma, 9 had ampullary carcinoma, and 8 had intrahepatic cholangiocarcinoma. Overall, 25 patients completed adjuvant chemotherapy, with a 54.3% completion rate while the completion rate without recurrence during the 1 year administration was 62.5%. Seven patients (15%) experienced adverse events (grade 3/4). The median number of courses administered was 7.5. Thirteen patients needed dose reduction or temporary therapy withdrawal. OS and DFS rates at 1/2 years were 91.2/80.0% and 84.3/77.2%, respectively. Among patients who were administered more than 3 courses of S-1, only one patient discontinued because of adverse events. Conclusions One-year administration of adjuvant S-1 therapy for resected BTC was feasible and may be a promising treatment for those with resected BTC. Now, a randomized trial to determine the optimal duration of S-1 is ongoing. Trial registration UMIN-CTR, UMIN000009029. Registered 5 October 2012-Retrospectively registered, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000009347

Abstract Background Chemotherapy with gemcitabine and cisplatin has been the standard of care in first-line chemotherapy for advanced biliary tract cancer (BTC) since the trial ABC-02 was published in 2010. We aimed to investigate the prognostic and predictive factors of this regimen in a cohort of Taiwanese patients with advanced BTC. Methods A total of 118 patients with histologically confirmed BTC treated at Chang Gung Memorial Hospital at Linkou from 2012 to 2017 were retrospectively reviewed. Results The median progression-free survival (PFS) and overall survival (OS) were 3.6 months and 8.4 months, respectively. In the multivariate analysis, neutrophil to lymphocyte ratio (NLR) > 7.45, biliary drainage requiring both percutaneous transhepatic cholangiography drainage (PTCD) and internal stenting, and tumor responses with progressive diseases and not assessed were independent poor prognostic factors for PFS. Male sex, NLR > 7.45, alkaline phosphatase> 94 U/L, biliary drainage requiring both PTCD and internal stenting, and tumor responses with stable disease, progressive diseases and not assessed were independent poor prognostic factors for OS. Monocyte to lymphocyte ratio (MLR) ≤ 0.28 was the only significant predictive factor for the tumor response. Patients with complete response/partial response had significantly lower MLR than patients with other tumor responses. Conclusion We identified three important prognostic factors, namely tumor response, NLR, and biliary drainage requiring both PTCD and internal stenting for both PFS and OS. MLR was the only significant predictive factor for the tumor response. These findings could provide physicians with more information to justify the clinical outcomes in patients with advanced BTC in real-world practice.

Abstract Background Currently, complete surgical resection represents the only potentially curative treatment option for Biliary Tract Cancer (BTC) including Gallbladder Cancer (GBC). Even after curative resection, 5-year OS is only 20–40%. Gallbladder carcinoma is relatively rare, but still the fifth most common neoplasm of the digestive tract and even the most frequent cancer of the biliary system. Gallbladder carcinoma is suspected preoperatively in only 30% of all pts., while the majority of cases are discovered incidentally by the pathologist after cholecystectomy for a benign indication. For improving curative rates in BTC and GBC, early systemic therapy combined with radical resection seems to be a promising approach. The earliest moment to apply chemotherapy would be in front of radical surgery. The encouraging results of neoadjuvant/perioperative concepts in other malignancies provide an additional rationale to use this treatment in the early phase of GBC management and even ICC/ECC. Especially because data regarding pure adjuvant chemotherapy in BTC’s are conflicting. Methods This is a multicenter, randomized, controlled, open-label phase III study including pts. with incidentally discovered GBCs after simple cholecystectomy in front of radical liver resection and pts. with resectable/ borderline resectable cholangiocarcinomas (ICC/ ECC) scheduled to receive perioperative chemotherapy (Gemcitabine + Cisplatin 3 cycles pre- and post-surgery) or surgery alone followed by a therapy of investigator’s choice. Primary endpoint is OS; secondary endpoints are PFS, R0-resection rate, toxicity, perioperative morbidity, mortality and QoL. A total of N = 333 patients with GBC or BTC will be included. Recruitment has started in August 2019. Discussion The current proposed phase III GAIN study investigates whether induction chemotherapy followed by radical resection in ICC/ECC and re-resection in IGBC (and – if possible – postoperative chemotherapy) prolongs overall survival compared to radical surgery alone for incidental gallbladder carcinoma and primary resectable or borderline resectable cholangiocarcinoma. Utilizing a neoadjuvant approach including a second radical surgery will help to raise awareness for the necessity of radical surgery, especially second radical completion surgery in IGBC and improve the adherence to the guidelines. Trial registration ClinicalTrials.gov ID: NCT03673072 from 17.09.2018. EudraCT number: 2017–004444-38 from 02.11.2017.

Abstract Background Cholangiocarcinoma is a rapidly fatal cancer entity with a median survival of less than one year. In contrast to many other malignancies, no substantial therapeutic breakthrough has been made in the past few decades, thereby limiting the treatment to cytotoxic chemotherapy with little beneficial effect for most patients. Targeted therapy tailored to the individual has shown substantial success in the recent past as a promising avenue for cancer therapy. Methods In this study, we determined the frequency of amplification of the HER2 gene in a comprehensive and well-characterized European cholangiocarcinoma cohort encompassing 436 patients including intrahepatic (n = 155), proximal (n = 155) and distal (n = 126) cholangiocarcinoma by strict application of a combined immunohistochemical and in situ hybridization algorithm following the current guidelines for HER2 assessment in gastric cancer. Results We identified a proportion of 1.4% (n = 6) patients that demonstrated HER2 gene amplification, with the highest rate among the distal cholangiocarcinoma patients (2.4%). None of the patients with equivocal (2+) immunohistochemical staining results exhibited gene amplification molecularly. In four of the five patients with HER2 positivity, gene amplification was already present in concomitantly tested high-grade biliary intraepithelial neoplasia (80%). HER2 gene amplification was not significantly associated with other clinical parameters, including survival. Conclusions This study identifies HER2 gene amplification as a rare event in cholangiocarcinoma of the Western population, occurring already in high-grade BilIN in a subset of patients. Furthermore, we provide a robust testing algorithm that may be used prior to therapy administration in future clinical trials evaluating the role of HER2 as a predictive marker in cholangiocarcinoma.

Background: Abnormal activation of the coagulation system has been reported in patients with malignancies, but its prognostic significance in biliary tract cancer (BTC) remains unclear. This study aims to analyze and compare the prognostic value of coagulation indices in patients with BTC.Methods: The medical records of 450 patients with BTC who underwent surgical resection at our hospital between 2003 and 2017 were retrospectively analyzed. Time-dependent receiver operating characteristic curves were plotted to compare the predictive accuracy of coagulation indices. A predictive nomogram for overall survival (OS) was established based on the Cox regression analysis and validated in both the training and validation cohorts. A novel stratification model was created according to the total points of the nomogram.Results: Fibrinogen and international normalized ratio (INR) had the best predictive accuracy among the coagulation indices considered and were also the independent prognostic factors for OS. The nomogram and the novel stratification model had satisfactory performance and outperformed TNM staging.Conclusions: The study demonstrated that coagulation indices are valuable in predicting OS in BTC, with fibrinogen and INR having the best predictive ability. The nomogram and the novel stratification model could be applied to predict survival for patients with BTC. [ABSTRACT FROM AUTHOR]

Abstract Background Biliary tract cancer (BTC) has a high mortality. Primary diagnosis is frequently delayed due to mostly unspecific symptoms, resulting in a high number of advanced cases at the time of diagnosis. Advanced BTCs are in principle chemotherapy sensitive as determined by improved disease control, survival and quality of life (QoL). However, median OS does not exceed 11.7 months with the current standard of care gemcitabine plus cisplatin. Thereby, novel drug formulations like nanoliposomal-irinotecan (nal-IRI) in combination with 5- fluorouracil (5-FU)/leucovorin may have the potential to improve therapeutic outcomes in this disease. Methods NIFE is an interventional, prospective, randomized, controlled, open label, two-sided phase II study. Within the study, 2 × 46 patients with locally advanced, non-resectable or metastatic BTC are to be enrolled by two stage design of Simon. Data analysis will be done unconnected for both arms. Patients are allocated in two arms: Arm A (experimental intervention) nal-IRI mg/m2, 46 h infusion)/5-FU (2400 mg/m2, 46 h infusion)/leucovorin (400 mg/m2, 0.5 h infusion) d1 on 14 day-cycles; Arm B (standard of care) cisplatin (25 mg/m2, 1 h infusion)/gemcitabine (1000 mg/m2, 0.5 h infusion) d1 and d8 on 21 day-cycles. The randomization (1:1) is stratified for tumor site (intrahepatic vs. extrahepatic biliary tract), disease stage (advanced vs. metastatic), age (≤70 vs. > 70 years), sex (male vs. female) and WHO performance score (ECOG 0 vs. ECOG 1). Primary endpoint of the study is the progression free survival (PFS) rate at 4 months after randomization by an intention-to-treat analysis in each of the groups. Secondary endpoints are the overall PFS rate, the 3-year overall survival rate, the disease control rate after 2 months, safety and patient related outcome with quality of life. The initial assessment of tumor resectability for locally advanced BTCs is planned to be reviewed retrospectively by a central surgical board. Exploratory objectives aim at establishing novel biomarkers and molecular signatures to predict response. The study was initiated January 2018 in Germany. Discussion The NIFE trial evaluates the potential of a nanoliposomal-irinotecan/5-FU/leucovorin combination in the first line therapy of advanced BTCs and additionally offers a unique chance for translational research. Trial registration Clinicaltrials.gov NCT03044587. Registration Date February 7th 2017.

Introduction: The present study aims to evaluate the efficacy and safety of apatinib monotherapy or combination therapy for patients with advanced or recurrent biliary tract cancer (BTC).Methods: Twenty-eight patients with advanced or recurrent BTC who progressed after prior systemic therapies and treated with apatinib from January 2017 to June 2019 were enrolled in this retrospective and observational study. The primary end point was progression free survival (PFS). Secondary end points included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and toxicity.Results: A total of 28 patients with advanced or recurrent BTC who progressed after prior systemic therapies received apatinib monotherapy or combination therapy (with capecitabine, S-1, oxaliplatin, irinotecan or PD-1 inhibitor), including 9 cases of gallbladder cancer and 19 cases of cholangiocarcinoma. Six patients achieved PR, 15 patients had SD and 7 patients had PD. Median progression-free survival (PFS) and overall survival (OS) was 4.3 months (95%CI = 1.8-6.8) and 6.2 months (95% CI = 4.6-7.8) respectively. The ORR and DCR were 21.4% (6/28) and 75.0% (21/28), respectively. Most of the adverse events were grade 1-2 in severity, apatinib treatment was well tolerated.Conclusions: Apatinib monotherapy or combination therapy can improve PFS in patients with advanced or recurrent BTC who progressed after prior systemic therapies, and adverse reactions can be well tolerated. Our study support apatinib therapy as a feasible therapeutic strategy in advanced or recurrent BTC. [ABSTRACT FROM AUTHOR]

Abstract Background Several intervention studies have demonstrated that exercise training has beneficial effects among cancer patients. However, older cancer patients are underrepresented in clinical trials, and only few exercise-based studies have focused specifically on older patients with cancer. In particular, research investigating the effects of exercise training among older patients with advanced cancer is lacking. The purpose of the current study is to investigate the effect of a 12-week multimodal and exercise-based intervention among older patients (≥65 years) with advanced pancreatic, biliary tract or lung cancer, who are treated with first-line palliative chemotherapy, immunotherapy or targeted therapy. Methods PACE-Mobil-PBL is a two-armed randomized controlled trial. Participants will be randomized 1:1 to an intervention group (N = 50) or a control group (N = 50). Participants in the intervention group will receive standard oncological treatment and a 12-week multimodal intervention, comprised of: (I) supervised exercise training, twice weekly in the hospital setting, (II) home-based walking with step counts and goal-setting, (III) supportive and motivational nurse-led counseling, and (IV) protein supplement after each supervised training session. Participants in the control group will receive standard oncological treatment. The primary outcome is physical function measured by the 30-s chair stand test. Secondary outcomes include measures of feasibility, activity level, physical capacity and strength, symptom burden, quality of life, toxicity to treatment, dose reductions, inflammatory biomarkers, body weight and composition, hospitalizations and survival. Assessments will be conducted at baseline, and after 6, 12 and 16 weeks. Discussion The current study is one of the first to investigate the effect of an exercise-based intervention specifically targeting older patients with advanced cancer. PACE-Mobil-PBL supports the development of health promoting guidelines for older patients with cancer, and the study results will provide new and valuable knowledge in this understudied field. Trial registration The study was prospectively registered at ClinicalTrials.gov on January 26, 2018 (ID: NCT03411200).

Abstract Background Recent studies have reported TIMs play an important role in tumors progression or regression, but the effect of TIMs in biliary tract cancer remains unclear. The aim of this study is to investigate the prognostic value of tumor infiltrating mast cells (TIMs) and its influence on gemcitabine-based adjuvant chemotherapy (ACT) benefits in biliary tract cancer patients after surgery. Methods TIMs were evaluated by immunohistochemical staining of tryptase in 250 patients with resected gallbladder carcinoma (GBC) or extrahepatic bile duct carcinoma (EBDC) from Zhongshan Hospital. The relationships between TIMs and clinicopathological factors and postoperative prognosis were analyzed respectively. Results High TIMs infiltration was significantly correlated with prolonged overall survival (OS). Furthermore, multivariate analysis indicated TNM stage and TIMs as independent prognostic factors for OS. Patients with high TIMs infiltration appeared to significantly benefit from Gemcitabine-based ACT in the discovery and validation cohorts. Spearman analysis identified that TIMs infiltration were positively correlated with anti-tumor CD8+ T cells. Conclusion TIMs infiltration is an independent favorable prognostic factor in GBC and EBDC patients, which could better stratify patients with different prognosis and predict benefit from gemcitabine-based ACT.

Abstract Background Biliary tract cancer (BTC) is a dismal disease, even after curative intent surgery. We conducted this prospective, non-randomized phase II study to evaluate the feasibility and efficacy of cisplatin and gemcitabine as adjuvant treatment in patients with resected BTC. Methods Patients initially received gemcitabine 1000 mg/m2 alone on days 1, 8 and 15 every 28-days for a total of six cycles (single agent cohort), and after protocol amendment a combination therapy with gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 on days 1 and 8 was administered every 21 days for a total of eight cycles (combined regimen cohort). Treatment was planned to start within eight weeks after curative intent resection. Adverse events, disease-free survival and overall survival were assessed. Results Overall 30 patients were enrolled in the study from August 2008 and last patient was enrolled at 2nd December 2014. The follow-up of the patients ended at 31st December 2016. The first 9 patients received single-agent gemcitabine. The interim analysis met the predefined feasibility criteria and, from September 2010 on, the second group of 21 patients received the combination of cisplatin plus gemcitabine. In the single-agent cohort with gemcitabine the median relative dose intensity (RDI) was 100% (IQR 88.3–100). Patients treated with the combination cisplatin-gemcitabine received an overall median RDI of 100% (IQR 50–100) for cisplatin and 100% (IQR 75–100) for gemcitabine respectively. The most significant non-hematological adverse events (grade 3 or 4) were fatigue (20%), infections during neutropenia (10%), and two cases of biliary sepsis (7%). Abnormal liver function was seen in 10% of the patients. One patient died due to infectious complications during treatment with cisplatin and gemcitabine. The median disease-free survival (DFS) was 14.9 months (95% CI 0–33.8) with a corresponding 3-year DFS of 43.1 ± 9.1%. The median overall survival (OS) was 40.6 months (95% CI 18.8–62.3) with a 3-year OS of 55.7 ± 9.2%. No statistically significant differences in survival were seen between the two treatment cohorts. Conclusion Adjuvant chemotherapy with gemcitabine with or without cisplatin was well tolerated and resulted in promising survival of the patients. Trial registration The study was retrospectively registered on 25th June 2009 at clinicaltrials.gov ( NCT01073839 ).

Background: Although surgery is the definitive curative treatment for biliary tract cancer (BTC), outcomes after surgery alone have not been satisfactory. Adjuvant therapy with S-1 may improve survival in patients with BTC. This study examined the safety and efficacy of 1 year adjuvant S-1 therapy for BTC in a multi-institutional trial.Methods: The inclusion criteria were as follows: histologically proven BTC, Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, R0 or R1 surgery performed, cancer classified as Stage IB to III. Within 10 weeks post-surgery, a 42-day cycle of treatment with S-1 (80 mg/m2/day orally twice daily on days 1-28 of each cycle) was initiated and continued up to 1 year post surgery. The primary endpoint was adjuvant therapy completion rate. The secondary endpoints were toxicities, disease-free survival (DFS), and overall survival (OS).Results: Forty-six patients met the inclusion criteria of whom 19 had extrahepatic cholangiocarcinoma, 10 had gallbladder carcinoma, 9 had ampullary carcinoma, and 8 had intrahepatic cholangiocarcinoma. Overall, 25 patients completed adjuvant chemotherapy, with a 54.3% completion rate while the completion rate without recurrence during the 1 year administration was 62.5%. Seven patients (15%) experienced adverse events (grade 3/4). The median number of courses administered was 7.5. Thirteen patients needed dose reduction or temporary therapy withdrawal. OS and DFS rates at 1/2 years were 91.2/80.0% and 84.3/77.2%, respectively. Among patients who were administered more than 3 courses of S-1, only one patient discontinued because of adverse events.Conclusions: One-year administration of adjuvant S-1 therapy for resected BTC was feasible and may be a promising treatment for those with resected BTC. Now, a randomized trial to determine the optimal duration of S-1 is ongoing.Trial Registration: UMIN-CTR, UMIN000009029. Registered 5 October 2012-Retrospectively registered, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000009347. [ABSTRACT FROM AUTHOR]

Background: Liver fibrosis or cirrhosis is associated with the dismal prognosis of hepatocellular carcinoma (HCC), and it might also be involved in intrahepatic cholangiocarcinoma (ICC). The effect of hepatic fibrosis on the survival of ICC patients is still unclear. This study aims to explore whether liver fibrosis impacts the overall survival (OS) and disease-specific survival (DSS) of ICC patients.Methods: Data of 729 eligible ICC patients receiving different therapies from the Surveillance, Epidemiology, and End Results database (2004-2015) were analyzed. Unmatched, propensity score-matched, and propensity score-weighted cohorts were used to investigate the relationships of different fibrosis scores (low fibrosis score vs. high fibrosis score) and survival. A Cox regression and Kaplan-Meier curves were used to explore the influence of fibrosis score on patients' survival. Stratified analyses based on treatment modality were conducted to compare the survival difference in ICC patients with different fibrosis scores.Results: Before matching, the one-, three-, and five-year OS were 50.9, 28.0, and 16.1% in the low fibrosis score group (n = 465) and 39.3, 20.1, and 8.0% in the high fibrosis score group (n = 264) (P < 0.001), respectively. After propensity score matching, the one-, three-, and five-year OS were 45.0, 26.0, and 10.2% in the low fibrosis score group and 36.0, 8.1, and 2.3% in the high fibrosis score group (P = 0.008), respectively. The multivariate Cox regression results showed that a high fibrosis score was an independent risk factor of OS. Additionally, patients with high fibrosis scores achieved low DSS after matching (P = 0.032). The survival benefits of the low fibrosis score group were consistent across treatment cohorts.Conclusions: High fibrosis scores were associated with poor clinical outcomes of ICC patients receiving different common therapies. [ABSTRACT FROM AUTHOR]

Background: FOLFIRINOX is a pillar first-line regimen in the treatment of pancreatic cancer. Historically, biliary tract cancer (BTC) and pancreatic cancer have been treated similarly with gemcitabine alone or combined with a platinum compound. With growing evidence supporting the role of fluoropyrimidines in the treatment of BTC, we aimed at assessing the outcomes of patients (pts) with BTC on frontline FOLFIRINOX.Methods: We retrospectively analyzed data of all our consecutive patients with locally advanced (LA) or metastatic (M) BTC who were registered to receive FOLFIRINOX as a first-line therapy between 12/2013 and 11/2017 at Paul Brousse university hospital. The main endpoints were Overall Survival (OS), Time-to-Progression (TTP), best Objective Response Rate (ORR), Disease Control rate (DCR), secondary macroscopically-complete resection (res) and incidence of severe (grade 3-4) toxicity (tox).Results: There were 17 male (40%) and 25 female (60%) pts. aged 36 to 84 years (median: 67). They had PS of 0 (55%) or 1 (45%), and intrahepatic cholangiocarcinoma (CCA) (21 pts., 50%), gallbladder carcinoma (8 pts., 19%), perihilar CCA (7 pts., 17%), distal CCA (4 pts., 10%) and ampulloma (2 pts., 5%). BTC was LA or M in 10 (24%) and 32 pts. (76%) respectively. Biliary stent was placed in 14 pts. (33%). A median of 10 courses was given with median treatment duration of 6 months. There were no untoward toxicity issues, with no febrile neutropenia, emergency admission for toxicity or toxic death. We observed 12 partial responses (29%) and 19 disease stabilisations (45%). Six patients (14%) underwent secondary R0-R1 resection. Median TTP was 8 months [95%CL, 6-10] and median OS was 15 months [13-17]. Patients undergoing secondary resection displayed a 3-y disease-free rate of 83%.Conclusions: First-line FOLFIRINOX offers promising results in patients with LA and M-BTC. It deserves prospective evaluation to further improve outcomes for advanced BTC. [ABSTRACT FROM AUTHOR]

Background: Chemotherapy with gemcitabine and cisplatin has been the standard of care in first-line chemotherapy for advanced biliary tract cancer (BTC) since the trial ABC-02 was published in 2010. We aimed to investigate the prognostic and predictive factors of this regimen in a cohort of Taiwanese patients with advanced BTC.Methods: A total of 118 patients with histologically confirmed BTC treated at Chang Gung Memorial Hospital at Linkou from 2012 to 2017 were retrospectively reviewed.Results: The median progression-free survival (PFS) and overall survival (OS) were 3.6 months and 8.4 months, respectively. In the multivariate analysis, neutrophil to lymphocyte ratio (NLR) > 7.45, biliary drainage requiring both percutaneous transhepatic cholangiography drainage (PTCD) and internal stenting, and tumor responses with progressive diseases and not assessed were independent poor prognostic factors for PFS. Male sex, NLR > 7.45, alkaline phosphatase> 94 U/L, biliary drainage requiring both PTCD and internal stenting, and tumor responses with stable disease, progressive diseases and not assessed were independent poor prognostic factors for OS. Monocyte to lymphocyte ratio (MLR) ≤ 0.28 was the only significant predictive factor for the tumor response. Patients with complete response/partial response had significantly lower MLR than patients with other tumor responses.Conclusion: We identified three important prognostic factors, namely tumor response, NLR, and biliary drainage requiring both PTCD and internal stenting for both PFS and OS. MLR was the only significant predictive factor for the tumor response. These findings could provide physicians with more information to justify the clinical outcomes in patients with advanced BTC in real-world practice. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: In the past four decades, the incidence of cholangiocarcinoma, especially intrahepatic cholangiocarcinoma (ICC), has raised rapidly worldwide. Completeness of resection, max size of tumor and etc. are widely recognized as prognostic factors. However, the prognosis significance of perineural invasion (PNI) on recurrence-free survival (RFS) and overall survival (OS) in ICC patients is controversial.Methods: ICC patients who underwent curative hepatectomy and diagnosed pathologically were retrospectively analyzed. Patients were grouped by existence of PNI and outcomes were compared between groups. The potential relationship between PNI and postoperative chemotherapy was also investigated.Results: There was no significant difference in demographic, clinical staging or tumor index between two groups, except positive hepatitis B surface antigen and CA19-9. PNI negative group showed a better prognosis in RFS (P < 0.0001) and OS (P < 0.0001). COX regression analyses showed PNI as an independent risk factor in RFS and OS. ICC with postoperative chemotherapy showed better effects in the whole cohort on both RFS (P = 0.0023) and OS (P = 0.0011). In PNI negative group, postoperative chemotherapy also showed significant benefits on RFS and OS, however not in PNI positive group (P = 0.4920 in RFS and P = 0.8004 in OS).Conclusion: PNI was an independent risk factor in R0-resected ICC, presenting worse recurrence and survival outcomes. Meanwhile, negative PNI may act as an indication of postoperative chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Tumor budding (TB) is used as an indicator of poor prognosis in various cancers. However, studies on TB in perihilar cholangiocarcinoma are still limited. We examined the significance of TB in resected perihilar cholangiocarcinoma with or without neoadjuvant therapy.Methods: Seventy-eight patients who underwent surgical resection at our institution for perihilar cholangiocarcinoma from 2004 to 2017, (36 with neoadjuvant therapy), were enrolled in this study. TB was defined as an isolated cancer cell or clusters (< 5 cells) at the invasive front and the number of TB was counted using a 20 times objective lens. Patients were classified into two groups according to TB counts: low TB (TB < 5) and high TB (TB ≥5).Results: In this 78 patient cohort, high TB was significantly associated with advanced tumor status (pT4: 50.0% vs 22.2%, p = 0.007, pN1/2: 70.8% vs 39.6%, p = 0.011, M1: 20.8% vs 1.9%) and higher histological grade (G3: 25.0% vs 5.7%, p = 0.014). Disease specific survival (DSS) in high TB was significantly inferior compared to that in low TB group (3-y DSS 14.5% vs 67.7%, p < 0.001). Interestingly, DSS in high TB showed similar to survival in unresected patients. In addition, high TB was also associated with advanced tumor status and poor prognosis in patients with neoadjuvant therapy. Multivariate analysis identified high TB as an independent poor prognostic factors for DSS (HR: 5.206, p = 0.001).Conclusion: This study demonstrated that high TB was strongly associated with advanced tumor status and poor prognosis in resected perihilar cholangiocarcinoma patients. High TB can be a novel poor prognostic factor in resected perihilar cholangiocarcinoma regardless of neoadjuvant therapy. [ABSTRACT FROM AUTHOR]

Background: Currently, complete surgical resection represents the only potentially curative treatment option for Biliary Tract Cancer (BTC) including Gallbladder Cancer (GBC). Even after curative resection, 5-year OS is only 20-40%. Gallbladder carcinoma is relatively rare, but still the fifth most common neoplasm of the digestive tract and even the most frequent cancer of the biliary system. Gallbladder carcinoma is suspected preoperatively in only 30% of all pts., while the majority of cases are discovered incidentally by the pathologist after cholecystectomy for a benign indication. For improving curative rates in BTC and GBC, early systemic therapy combined with radical resection seems to be a promising approach. The earliest moment to apply chemotherapy would be in front of radical surgery. The encouraging results of neoadjuvant/perioperative concepts in other malignancies provide an additional rationale to use this treatment in the early phase of GBC management and even ICC/ECC. Especially because data regarding pure adjuvant chemotherapy in BTC's are conflicting.Methods: This is a multicenter, randomized, controlled, open-label phase III study including pts. with incidentally discovered GBCs after simple cholecystectomy in front of radical liver resection and pts. with resectable/ borderline resectable cholangiocarcinomas (ICC/ ECC) scheduled to receive perioperative chemotherapy (Gemcitabine + Cisplatin 3 cycles pre- and post-surgery) or surgery alone followed by a therapy of investigator's choice. Primary endpoint is OS; secondary endpoints are PFS, R0-resection rate, toxicity, perioperative morbidity, mortality and QoL. A total of N = 333 patients with GBC or BTC will be included. Recruitment has started in August 2019.Discussion: The current proposed phase III GAIN study investigates whether induction chemotherapy followed by radical resection in ICC/ECC and re-resection in IGBC (and - if possible - postoperative chemotherapy) prolongs overall survival compared to radical surgery alone for incidental gallbladder carcinoma and primary resectable or borderline resectable cholangiocarcinoma. Utilizing a neoadjuvant approach including a second radical surgery will help to raise awareness for the necessity of radical surgery, especially second radical completion surgery in IGBC and improve the adherence to the guidelines.Trial Registration: ClinicalTrials.gov ID: NCT03673072 from 17.09.2018. EudraCT number: 2017-004444-38 from 02.11.2017. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) with hilar bile duct tumor thrombus (HBDTT) often mimic hilar cholangiocarcinoma (hilar CC). The purpose of this study is to analyze the Computed Tomography (CT) characteristics of HCC with HBDTT and to identify imaging features to aid its differentiation from hilar CC on enhanced CT.Methods: We retrospectively identified 58 cases with pathologically proved HCC with HBDTT between 2011 and 2018. Seventy-seven cases of pathologically proven hilar CCs were selected during the same period. The clinical features and CT findings of the two groups were reviewed and compared.Results: HCC with HBDTTs are more commonly found in men (87.9% vs 63.6%, p = 0.001) with lower age of onset (49.84 vs 58.61 years; p < 0.001) in comparison to hilar CCs. Positive correlation were identified between HCC with HBDTTs and chronic HBV infection (72.4% vs 11.7%; p <  0.001), increased serum AFP (67.2% vs 1.3%; p <  0.001), CA19-9 level (58.6% vs 85.7%; p <  0.001) and CEA level (3.4% vs 29.9%; p = 0.001), parenchymal lesion with intraductal lesion (100% vs 18.2%; p <  0.001), washout during the portal venous phase (84.5% vs 6.5%; p <  0.001), thickened bile duct wall (8.6% vs 93.5%; p <  0.001), intrahepatic vascular embolus (44.8% vs 7.8%; p <  0.001), splenomegaly (34.5% vs 2.6%, p <  0.001). A scoring system consisting of the five parameters obtained from characteristics mentioned above was trialed. The sensitivity and specificity for diagnosing HCC with HBDTT were 96.39, 100 and 92.5% respectively when the total score was 2 or more.Conclusions: HCC with HBDTTs are often distinguishable from hilar CCs based on washout during portal venous phase without thickened bile duct wall. HBV infection and serum AFP level facilitate the differentiation. [ABSTRACT FROM AUTHOR]

Background: To explore the patterns of failures and areas at highest risk of recurrence for postoperative intrahepatic cholangiocarcinoma (IHCC), with the aim to guide IHCC adjuvant radiotherapy.Methods: Patients with IHCC who had undergone radical surgery at our institution from July 2010 to August 2017 were retrospectively analyzed. The survival and prognostic factors were analyzed by univariate and multivariate analysis. All sites of recurrence were found out and classified as the surgical margin, regional lymph nodes, liver remnant and distant metastasis. According to the recurring area at highest risk, the target volume of adjuvant radiotherapy was proposed.Results: The median follow-up time was 23.5 months (2-85 months). The median recurrence free survival (RFS) and overall survival (OS) were 12.1 months and 24.8 months, respectively. Seventy-three (73/127, 57.5%) IHCC patients developed tumor recurrence. Initial recurrences occurred in the potential postoperative radiotherapy (PORT) volume, remnant liver and distant sits were 46 (46/73, 63.0%), 36 (36/73, 49.3%) and 22 (22/73, 30.1%) cases, respectively. Of the 46 patients whose initial recurrence inside the potential PORT volume, 29 (29/73, 39.7%) developed recurrence only inside the potential PORT volume, including 13 tumor bed recurrences, 7 lymph node metastases, and 9 with both tumor bed recurrences and lymph node metastases. The most common lymph node metastases sites were nodes around the abdominal aorta, followed by lymph nodes along the celiac artery, the common hepatic artery, and in the hepatoduodenal ligament.Conclusions: High proportion of the recurrences occurred only inside the potential PORT volume, implying adjuvant radiotherapy might improve the local-regional control. Surgical margins and lymph node stations No.16a2, 9, 8, 12, 13, and 14 are suggested to be included in the radiation volume. [ABSTRACT FROM AUTHOR]

Background: Several intervention studies have demonstrated that exercise training has beneficial effects among cancer patients. However, older cancer patients are underrepresented in clinical trials, and only few exercise-based studies have focused specifically on older patients with cancer. In particular, research investigating the effects of exercise training among older patients with advanced cancer is lacking. The purpose of the current study is to investigate the effect of a 12-week multimodal and exercise-based intervention among older patients (≥65 years) with advanced pancreatic, biliary tract or lung cancer, who are treated with first-line palliative chemotherapy, immunotherapy or targeted therapy.Methods: PACE-Mobil-PBL is a two-armed randomized controlled trial. Participants will be randomized 1:1 to an intervention group (N = 50) or a control group (N = 50). Participants in the intervention group will receive standard oncological treatment and a 12-week multimodal intervention, comprised of: (I) supervised exercise training, twice weekly in the hospital setting, (II) home-based walking with step counts and goal-setting, (III) supportive and motivational nurse-led counseling, and (IV) protein supplement after each supervised training session. Participants in the control group will receive standard oncological treatment. The primary outcome is physical function measured by the 30-s chair stand test. Secondary outcomes include measures of feasibility, activity level, physical capacity and strength, symptom burden, quality of life, toxicity to treatment, dose reductions, inflammatory biomarkers, body weight and composition, hospitalizations and survival. Assessments will be conducted at baseline, and after 6, 12 and 16 weeks.Discussion: The current study is one of the first to investigate the effect of an exercise-based intervention specifically targeting older patients with advanced cancer. PACE-Mobil-PBL supports the development of health promoting guidelines for older patients with cancer, and the study results will provide new and valuable knowledge in this understudied field.Trial Registration: The study was prospectively registered at ClinicalTrials.gov on January 26, 2018 (ID: NCT03411200 ). [ABSTRACT FROM AUTHOR]

Background: Biliary tract cancer (BTC) is a dismal disease, even after curative intent surgery. We conducted this prospective, non-randomized phase II study to evaluate the feasibility and efficacy of cisplatin and gemcitabine as adjuvant treatment in patients with resected BTC.Methods: Patients initially received gemcitabine 1000 mg/m2 alone on days 1, 8 and 15 every 28-days for a total of six cycles (single agent cohort), and after protocol amendment a combination therapy with gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 on days 1 and 8 was administered every 21 days for a total of eight cycles (combined regimen cohort). Treatment was planned to start within eight weeks after curative intent resection. Adverse events, disease-free survival and overall survival were assessed.Results: Overall 30 patients were enrolled in the study from August 2008 and last patient was enrolled at 2nd December 2014. The follow-up of the patients ended at 31st December 2016. The first 9 patients received single-agent gemcitabine. The interim analysis met the predefined feasibility criteria and, from September 2010 on, the second group of 21 patients received the combination of cisplatin plus gemcitabine. In the single-agent cohort with gemcitabine the median relative dose intensity (RDI) was 100% (IQR 88.3-100). Patients treated with the combination cisplatin-gemcitabine received an overall median RDI of 100% (IQR 50-100) for cisplatin and 100% (IQR 75-100) for gemcitabine respectively. The most significant non-hematological adverse events (grade 3 or 4) were fatigue (20%), infections during neutropenia (10%), and two cases of biliary sepsis (7%). Abnormal liver function was seen in 10% of the patients. One patient died due to infectious complications during treatment with cisplatin and gemcitabine. The median disease-free survival (DFS) was 14.9 months (95% CI 0-33.8) with a corresponding 3-year DFS of 43.1 ± 9.1%. The median overall survival (OS) was 40.6 months (95% CI 18.8-62.3) with a 3-year OS of 55.7 ± 9.2%. No statistically significant differences in survival were seen between the two treatment cohorts.Conclusion: Adjuvant chemotherapy with gemcitabine with or without cisplatin was well tolerated and resulted in promising survival of the patients.Trial Registration: The study was retrospectively registered on 25th June 2009 at clinicaltrials.gov ( NCT01073839 ). [ABSTRACT FROM AUTHOR]

Background: Outcomes in younger (<40 years) and elderly (≥70 years) patients with advanced biliary cancer (ABC) receiving palliative chemotherapy are unclear. This study assessed outcomes in those receiving monotherapy or combination therapy in thirteen prospective systemic-therapy trials.Methods: Multivariable analysis explored the impact of therapy on progression-free (PFS) and overall survival (OS) in two separate age cohort groups: <70 years and ≥70 years, and <40 years and ≥40 years.Results: Overall, 1163 patients were recruited (Jan 1997-Dec 2013). Median age of entire cohort: 63 years (range 23-85); 36 (3%) were <40, 260 (22%); ≥70. Combination therapy was platinum-based in nine studies. Among patients <40 and ≥70 years, 23 (64%) and 182 (70%) received combination therapy, respectively. Median follow-up was 42 months (95%-CI 37-51). Median PFS for patients <40 and ≥40 years was 3.5 and 5.9 months (P = 0.12), and OS was 10.8 and 9.7 months, respectively (P = 0.55). Median PFS for those <70 and ≥70 years was 6.0 and 5.0 months (P = 0.53), and OS was 10.2 and 8.8 months, respectively (P = 0.08). For the entire cohort, PFS and OS were significantly better in those receiving combination therapy: Hazard Ratio [HR]-0.66, 95%-CI 0.58-0.76, P < 0.0001 and HR-0.72, 95%-CI 0.63-0.82, P < 0.0001, respectively; and in patients ≥70 years: HR-0.54 (95%-CI 0.38-0.77, P = 0.001) and HR-0.60 (95%-CI 0.43-0.85, P = 0.004), respectively. There was no evidence of interaction between age and treatment for PFS (P = 0.58, P = 0.66) or OS (P = 0.18, P = 0.75).Conclusions: In ABC, younger patients are rare, and survival in elderly patients in receipt of systemic therapy for advanced disease, whether monotherapy or combination therapy, is similar to that of non-elderly patients, therefore age alone should not influence decisions regarding treatment. [ABSTRACT FROM AUTHOR]

Background: Combined treatment with cisplatin and gemcitabine (CisGem) is the standard of care for patients with advanced biliary tract cancer (ABC). Selumetinib (AZD6244, ARRY-142886) potently and selectively inhibits MEK1/2, an intracellular kinase and has shown activity in ABC. The objective of the ABC-04 trial was to establish the recommended dose of selumetinib in combination with CisGem in patients with ABC.Methods: Eligible patients were ≥ 18 years, had histologically or cytologically-confirmed unresectable recurrent or metastatic biliary tract, gallbladder or ampullary carcinoma, WHO performance status 0-2, and adequate major organ function. Patients may have had prior surgery, radiotherapy or adjuvant chemotherapy, but no prior CisGem and no prior chemotherapy for locally advanced or metastatic disease. Patients received cisplatin 25 mg/m(2) plus gemcitabine 1000 mg/m(2) intravenously on days 1 and 8 of a 21-day cycle. Selumetinib capsules were taken daily. Patients received up to 8 cycles of CisGem and could receive selumetinib until disease progression. A dose de-escalation scheme was used to determine the recommended dose of selumetinib. The first dose level was 75 mg bd. Patients were recruited in cohorts of 3 and assessed for dose limiting toxicity (DLT) during the first cycle of treatment.Results: Thirteen patients were recruited, of whom 12 were evaluable for DLT (1 did not start treatment). All evaluable patients received the starting dose of selumetinib 75 mg bd and one patient experienced a DLT (cardiac chest pain). The median number of days selumetinib was taken (adjusted for the number of days of dose interruptions) was 171.5 (IQR: 75.5 to 344). Two patients remained on treatment at 14 and 19 months post registration. There were 3 temporary and 1 permanent interruptions of selumetinib in cycle 1. Eight patients were evaluable for objective response (RECIST v1.1): 3 had a partial response and 5 stable disease. The median PFS was 6.4 months (IQR 5.2 to 13.7). Toxicities related to selumetinib were mostly related to oedema and rash, grade 1-2 and manageable. Pharmacokinetic analysis showed that the AUC(0-t), AUC(0-∞) and Cmax of selumetinib increased by 12, 11 and 30 % respectively when it was administered with CisGem, while Cmax for the N-desmethyl metabolite of selumetinib decreased by 40 %. There was no evidence that the time of Cmax for selumetinib or N-desmethyl metabolite of selumetinib were different when selumetinib was administered alone or with CisGem.Conclusion: The recommended dose of selumetinib when combined with CisGem was 75 mg bd. Translational studies are underway to identify biomarkers that may predict outcome (ClinicalTrials.gov identifier: NCT01242605 July 6(th) 2010). [ABSTRACT FROM AUTHOR]