Abstract
The treatment of unresectable cholangiocarcinoma (CCA) is limited by the development of resistance to conventional first-line chemotherapy based on gemcitabine (GEM). In addition, a prior treatment with GEM frequently induces cross-resistance to other drugs employed in the second-line. Paclitaxel (PTX) is now emerging as an alternative option for the management of advanced/metastatic CCA. In the present work, we evaluate the antitumor activity of PTX in preclinical models of multidrug-resistant intrahepatic cholangiocarcinoma (iCCA). In vitro, PTX decreases tumor cell viability by affecting the cell cycle and inducing apoptosis and impairs the stem cell compartment. In vivo, a therapeutic regimen containing albumin-bound nanoparticle (Nab)-PTX overcomes drug resistance resulting in delayed tumor growth, impaired organization of the tumor vasculature, and reduced glucose uptake. Together, our results provide a rationale to consider PTX-based regimens in patients with iCCA who became refractory to conventional therapies.
Highlights
Cholangiocarcinomas (CCAs) are heterogeneous biliary epithelial tumors arising from the intrahepatic, perihilar, or distal biliary tree epithelium [1]
In a retrospective analysis on 321 patients previously treated with first-line GEM–cisplatin, the overall response rate (ORR) to second-line FP-based chemotherapy was as low as 3%, the median progression-free survival (PFS) 1.9 months only, and the median overall survival (OS) 6.5 months [11]
We demonstrated that both primary and acquired GEM resistance confer cross-resistance to other chemotherapeutics, including 5-FU in addition to carboplatin and trabectedin [13, 14], which could explain the disappointing outcome of conventional second-line therapy in CCA patients
Summary
Cholangiocarcinomas (CCAs) are heterogeneous biliary epithelial tumors arising from the intrahepatic (iCCA), perihilar (pCCA), or distal biliary (dCCA) tree epithelium [1]. Paclitaxel and Gemcitabine in Cholangiocarcinoma symptoms, diagnosis often occurs at an advanced stage, resulting in poor prognosis and in a 5-year survival rate of ~10% [2]. The unavailability of molecular markers for early diagnosis, the limited therapeutic options, and the absence of effective targeted therapies remain the major clinical hurdles in CCA management. In a retrospective analysis on 321 patients previously treated with first-line GEM–cisplatin, the overall response rate (ORR) to second-line FP-based chemotherapy was as low as 3%, the median progression-free survival (PFS) 1.9 months only, and the median overall survival (OS) 6.5 months [11]. We demonstrated that both primary and acquired GEM resistance confer cross-resistance to other chemotherapeutics, including 5-FU in addition to carboplatin and trabectedin [13, 14], which could explain the disappointing outcome of conventional second-line therapy in CCA patients
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