Optimization of systemic treatments for patients with biliary tract cancer

Biliary tract cancer (BTC) is a malignancy of the intrahepatic and extrahepatic bile ducts, including the gallbladder. BTC is diagnosed in approximately 1,000 patients annually in the Netherlands. The majority of patients are diagnosed at an advanced stage. Before the publication of the landmark ABC-02 trial in 2010, there were no standard systemic treatments for BTC. Over the past decade, there has been a substantial increase in the number of conducted clinical trials for BTC. Despite this, limited treatment options are available, all of which provide limited survival benefits. Real-world data is highly relevant to validate the results of clinical trials in daily practice and to monitor the quality of care in daily practice. The main aim of this thesis was to evaluate the effectiveness of available systemic treatments in daily practice using population-based data, and to identify subgroups of patients that may benefit most from these treatments. Additionally, we aimed to study the feasibility and efficacy of fluorouracil, leucovorin, irinotecan plus oxaliplatin (FOLFIRINOX) as a second-line treatment for biliary tract cancer

Optimization of systemic treatments for patients with biliary tract cancer

Biliary tract cancer (BTC) is a malignancy of the intrahepatic and extrahepatic bile ducts, including the gallbladder. BTC is diagnosed in approximately 1,000 patients annually in the Netherlands. The majority of patients are diagnosed at an advanced stage. Before the publication of the landmark ABC-02 trial in 2010, there were no standard systemic treatments for BTC. Over the past decade, there has been a substantial increase in the number of conducted clinical trials for BTC. Despite this, limited treatment options are available, all of which provide limited survival benefits. Real-world data is highly relevant to validate the results of clinical trials in daily practice and to monitor the quality of care in daily practice. The main aim of this thesis was to evaluate the effectiveness of available systemic treatments in daily practice using population-based data, and to identify subgroups of patients that may benefit most from these treatments. Additionally, we aimed to study the feasibility and efficacy of fluorouracil, leucovorin, irinotecan plus oxaliplatin (FOLFIRINOX) as a second-line treatment for biliary tract cancer

Prognostic and predictive value of human equilibrative nucleoside transporter 1 (hENT1) in extrahepatic cholangiocarcinoma:a translational study

Introduction: Effective (neo) adjuvant chemotherapy for cholangiocarcinoma is lacking due to chemoresistance and the absence of predictive biomarkers. Human equilibrative nucleoside transporter 1 (hENT1) has been described as a potential prognostic and predictive biomarker. In this study, the potential of rabbit-derived (SP120) and murine-derived (10D7G2) antibodies to detect hENT1 expression was compared in tissue samples of patients with extrahepatic cholangiocarcinoma (ECC), and the predictive value of hENT1 was investigated in three ECC cell lines.Methods: Tissues of 71 chemonaïve patients with histological confirmation of ECC were selected and stained with SP120 or 10D7G2 to assess the inter-observer variability for both antibodies and the correlation with overall survival. Concomitantly, gemcitabine sensitivity after hENT1 knockdown was assessed in the ECC cell lines EGI-1, TFK-1, and SK-ChA-1 using sulforhodamine B assays.Results: Scoring immunohistochemistry for hENT1 expression with the use of SP120 antibody resulted in the highest interobserver agreement but did not show a prognostic role of hENT1. However, 10D7G2 showed a prognostic role for hENT1, and a potential predictive role for gemcitabine sensitivity in hENT1 in SK-ChA-1 and TFK-1 cells was found.Discussion: These findings prompt further studies for both preclinical validation of the role of hENT1 and histochemical standardization in cholangiocarcinoma patients treated with gemcitabine-based chemotherapy

Advances in adjuvant therapy of biliary tract cancer: an overview of current clinical evidence based on phase II and III trials

Patients with biliary tract cancer (BTC) have a high recurrence rate after complete surgical resection. To reduce the risk of recurrence and to improve survival, several chemotherapeutic agents that have shown to be active in locally advanced and metastatic BTC have been investigated in the adjuvant setting in prospective clinical trials. Based on the results of the BILCAP phase III trial, capecitabine was adapted as the standard of care by the ASCO clinical practice guideline. Ongoing randomized controlled trials mainly compare capecitabine with gemcitabine-based chemotherapy or chemoradiotherapy. This review provides an update of adjuvant therapy in BTC based on published data of phase II and III trials and ongoing randomized controlled trials (RCTs)

Treatment and survival of resected and unresected distal cholangiocarcinoma: a nationwide study

Background: Population-based data on distal cholangiocarcinoma (DCC) from the Western world are not available, albeit essential to identify areas for improvement. This study investigated the incidence, treatment and outcomes, including time trends and predictors for survival, in a nationwide cohort of DCC. Methods: This is a retrospective cohort study of patients diagnosed with DCC (2009–2016) derived from the Netherlands Cancer Registry. Overall survival (OS) and its predictors were analyzed using Kaplan–Meier and Cox regres

Efficacy and safety of systemic induction therapy in initially unresectable locally advanced intrahepatic and perihilar cholangiocarcinoma: A systematic review

Background: According to international guidelines, induction therapy may be considered in selected patients with initially unresectable locally advanced cholangiocarcinoma. The criteria for (un)resectability in cholangiocarcinoma varies between studies and no consensus-based agreement is available about these criteria. By performing a systematic literature review, we aimed to investigate the efficacy and safety of systemic induction therapy in initially unresectable locally advanced perihilar (pCCA) and intrahepatic cholangiocarcinoma (iCCA) and summarize resectability criteria used across studies. Methods: A literature search was performed in PubMed, EMBASE, Web of Science and Cochrane library to identify studies on systemic induction therapy in locally advanced pCCA and/or iCCA. The primary outcome was resection rate (RR) after induction therapy and secondary outcomes were overall survival (OS) and objective response rate (ORR). Results: Ten studies with a total of 1167 patients met the inclusion criteria and were included in this review. Among these patients, 334 (28.6%) were treated with systemic induction therapy. Across the studies, different types of chemotherapy regimens were administered (e.g., gemcitabine (based) chemotherapy and 5-FU (based) chemotherapy). Only six studies provided sufficient data and were used to analyze pooled (radical) resection rates. After induction therapy, 94 patients (39.2%) underwent a resection, of which R0 resections (22.9%). Pooled data on OS showed, better OS for chemotherapy plus resection versus chemotherapy only (pooled HR = 0.31, 95% CI = 0.19–0.50; P value < 0.0001). Conclusion: Adequately selected patients with locally advanced pCCA or iCCA may benefit from induction therapy followed by surgical resection. Prospective randomized controlled trials are warranted

Efficacy and safety of FOLFIRINOX as salvage treatment in advanced biliary tract cancer:an open-label, single arm, phase 2 trial

Background: No standard treatment is available for advanced biliary tract cancer (BTC) after first-line therapy with gemcitabine plus cisplatin (GEMCIS). The objective of this study was to evaluate safety and anti-tumour activity of fluorouracil, leucovorin, irinotecan plus oxaliplatin (FOLFIRINOX) as salvage treatment in patients with previously treated advanced BTC. Methods: In this two-stage phase 2 study, patients with advanced BTC who had disease progression or unacceptable toxicity after ≥3 cycles of GEMCIS were eligible. Primary endpoints were safety and efficacy (defined as objective response rate, ORR). In stage one, ten patients were treated with FOLFIRINOX every 2 weeks. In stage two, an additional 20 patients were enrolled at a starting dose as defined in stage one, provided that in stage ≥1 objective response or ≥2 stable diseases were observed and ≤3 patients had serious adverse events (SAEs) within the first 6 weeks of treatment. Secondary endpoints were progression-free survival (PFS) and overall survival (OS). Results: Forty patients were screened for eligibility and 30 patients were enrolled. In stage one, one patient had a partial response and five patients had stable disease. One patient had a SAE during the first 6 weeks of treatment, and five patients required a dose reduction due to adverse events. The most common grade 3–4 adverse events in stage one were neutropaenia, mucositis and diarrhoea. Stage two was initiated with FOLFIRINOX in an adapted dose. In stage two, grade 3–4 neutropaenia, diarrhoea, nausea and vomiting were the most common adverse events. The ORR, median PFS and OS in all patients were 10%, 6.2 and 10.7 months, respectively. Conclusions: In patients with advanced BTC who progressed after or were intolerant to GEMCIS, FOLFIRINOX can be administered safely and could be considered as an option for salvage treatment in these patients. Clinical trial registration: ClinicalTrials.gov Identifier NCT02456714