Cholangiocarcinoma — evolving concepts and therapeutic strategies

Abstract

Cholangiocarcinoma is a disease entity comprising diverse epithelial tumours with features of cholangiocyte differentiation: cholangiocarcinomas are categorized according to anatomical location as intrahepatic (iCCA), perihilar (pCCA), or distal (dCCA). Each subtype has a distinct epidemiology, biology, prognosis, and strategy for clinical management. The incidence of cholangiocarcinoma, particularly iCCA, has increased globally over the past few decades. Surgical resection remains the mainstay of potentially curative treatment for all three disease subtypes, whereas liver transplantation after neoadjuvant chemoradiation is restricted to a subset of patients with early stage pCCA. For patients with advanced-stage or unresectable disease, locoregional and systemic chemotherapeutics are the primary treatment options. Improvements in external-beam radiation therapy have facilitated the treatment of cholangiocarcinoma. Moreover, advances in comprehensive whole-exome and transcriptome sequencing have defined the genetic landscape of each cholangiocarcinoma subtype. Accordingly, promising molecular targets for precision medicine have been identified, and are being evaluated in clinical trials, including those exploring immunotherapy. Biomarker-driven trials, in which patients are stratified according to anatomical cholangiocarcinoma subtype and genetic aberrations, will be essential in the development of targeted therapies. Targeting the rich tumour stroma of cholangiocarcinoma in conjunction with targeted therapies might also be useful. Herein, we review the evolving developments in the epidemiology, pathogenesis, and management of cholangiocarcinoma.

A phase 2 trial of regorafenib as a single agent in patients with chemotherapy‐refractory, advanced, and metastatic biliary tract adenocarcinoma

“…13 These advances in comprehensive whole-exome and transcriptome sequencing have defined the genetic landscape of each cholangiocarcinoma subtype, and potential promising molecular targets for precision medicine are being evaluated in clinical trials, 25 including those exploring immunotherapy. Thirtyfive percent of patients had received more than 2 lines of systemic treatments before the study.…”

“…22 The toxicity of the standard 160-mg regorafenib regime has resulted in the clinical use of various dose modifications, including dose reductions and interruptions. 23,25 Hypophosphatemia is one of the most common toxicities of regorafenib, with 5% to 9% rates of grade ≥3 toxicities reported in phase 3 studies. 39 The other study that analyzed data from patients with mCRC used different regorafenib starting doses: 54% of patients received 160 mg, 40% received 120 mg, and 6% received 80 mg. 40 Those results indicated that various starting doses had no association with survival in univariate or multivariate analysis.…”

The role of minimally invasive hepatectomy for hilar and intrahepatic cholangiocarcinoma: A systematic review of the literature

“…Cholangiocarcinomas are neoplasms arising from epithelial cells of the biliary tract, and are the second most common primary liver malignancy . They can be divided according to their anatomical location.…”

“…Accounting for only 3% of gastrointestinal malignancies, they are aggressive tumors usually marked by late diagnosis and poor outcomes . Surgery is still the most effective therapy available, and a complete tumor resection is important to achieve long‐term survival …”

Identification of a Pan‐Gamma‐Secretase Inhibitor Response Signature for Notch‐Driven Cholangiocarcinoma

“…No clear indications for second‐line chemotherapy exist. Given the limited survival advantage of GemCis, it has been suggested that some patients should be enrolled in experimental trials in place of standard‐of‐care . Any experimental trials should require careful biomarker‐driven stratification of prospective responders, given the potential of individual driver mutations to influence diverse pharmacologic responses .…”