Will advanced cholangiocarcinoma become a targetable malignancy?
Graphical abstract
Introduction
Cholangiocarcinomas (CC) are a group of heterogenous biliary tract tumors, essentially adenocarcinomas, that can be intrahepatic or extrahepatic (perihilar or distal) with the exclusion of gallbladder cancer and ampulla of Vater’s cancer. They are more frequently extrahepatic with perihilar disease as the predominant type. Over the past two decades, for unknown reasons, the incidence of intrahepatic CC (which was initially around 10 % of CC) has been increasing in Western countries (Yang et al., 2012).
CC are relatively rare but lethal because the only potential cure available is surgery and only a minority of patients presents with an early and resectable disease. Distal CC have the highest resectability rates. Even if surgery is feasible, outcomes are poor particularly with node positive diseases due to the high risk of local and distal recurrences (Blechacz, 2017).
In advanced disease, median survival is less than 2 years with a poor overall prognosis (Global, 2015). Because of the paucity of clinical trials studying CC, there is no standard, guideline-approved treatment for advanced CC. Systemic chemotherapy and treatment for metastatic CC and locally advanced non resectable CC have traditionally been proposed by extrapolation from data and treatment strategies of pancreatic and hepatic cancer. However, since the description of a variety of molecular defects involving oncogenes and tumor suppressor genes, inducing the conversion of cholangiocarcinoma’s precursors (intraductal papillary mucinous neoplasm and biliary intraepithelial neoplasia) to a malignant tumor, by a stepwise accumulation of genetic abnormalities (Aljabban et al., 2020), clinical trials have been designed to study the molecular identity of the CC and to explore targeted therapy (Zen et al., 2007; Schlitter et al., 2014).
Despite evolving molecular research and techniques, the molecular pathogenesis of CC is still less understood than that of other Gastrointestinal tumors. The aim of this review is to explore and describe new targeted medications and therapeutic strategies that could radically change the prognosis of this fatal cancer and enhance the quality of life of patients.
Section snippets
Material and methods
In order to review the newest treatment options explored in advanced CC, an extensive electronic search of the literature was conducted in the PubMed database until the 22th of July 2020. The following keywords with Boolean operators were used ‘advanced cholangiocarcinoma’, ' advanced biliary tract cancer’, ‘immunotherapy’ and ‘targeted therapy' in combination with ‘genetic aberrations’, ‘molecular pathways’. A total of 524 articles were extracted. Articles emphasizing on treatment of liver
Current trend in Cholangiocarcinoma treatment
Currently, and despite many new clinical trials evaluating targeted therapy, the standard of care for advanced cholangiocarcinoma is still the combination of gemcitabine and cisplatin in patients with good performance status, with limited therapeutic efficacy.
As cited above, a variety of molecular defects involved in CC pathogenesis were recognized and explored. In order to discover the limited number of targetable mutations, a sensitive and specific sequencing is necessary to detect all
Discussion
A detailed and extensive review of all trials and publications available demonstrated potential treatments for this previously uncurable cancer because of a wide array of targetable genetic aberrations implicated in its carcinogenesis pathway.
The main limitation of those treatments until now, is the paucity of phase III randomized comparative results and clinical practice implementation. Moreover, treatment options are mainly evaluated in trials for all type of advanced biliary cancer including
Fundings
None.
CRediT authorship contribution statement
Yara Sarkis: Conceptualization, Data curation, Investigation, Methodology, Resources, Visualization, Writing - original draft, Writing - review & editing. Amine Al Soueidy: Data curation, Investigation, Resources, Writing - review & editing. Hampig Raphael Kourie: Conceptualization, Project administration, Supervision, Methodology, Validation, Writing - review & editing.
Declaration of Competing Interest
The authors report no declarations of interest.
Yara Sarkis: 26 years old Lebanese doctor. She graduated from medical school at Saint Joseph University in 2019 ranked third. She is currently a PGY-2 Internal Medicine Resident at Hotel Dieu De France Hospital. She is interested in Gastroenterology and Hepatology. She has completed the first part of a Medical Research Master at her university and has worked on various research projects.
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Cited by (0)
Yara Sarkis: 26 years old Lebanese doctor. She graduated from medical school at Saint Joseph University in 2019 ranked third. She is currently a PGY-2 Internal Medicine Resident at Hotel Dieu De France Hospital. She is interested in Gastroenterology and Hepatology. She has completed the first part of a Medical Research Master at her university and has worked on various research projects.
Amine Al Soueidy: 26 years old Lebanese doctor. He graduated from medical school at Saint Joseph University in 2019 ranked first. He is currently a PGY-2 Ophthalmology Resident at Hotel Dieu De France Hospital. He has completed the first part of a Medical Research Master at his university and has worked on various research projects.
Hampig Raphael Kourie: Lebanese doctor working as a physician at different major hospital in Lebanon (Belle-Vue Medical Center, Saint Joseph Hospital, and Hotel Dieu De France Hospital). He got his Medical Degree and his specialty diploma in Hematology-Oncology from Saint Joseph University and completed a fellowship in Digestive Oncology at Georges Pompidou European Hospital in France.