Targeted Therapies for Perihilar Cholangiocarcinoma

Abstract

Perihilar cholangiocarcinoma (pCCA) is the anatomical sub-group of biliary tract cancer (BTC) arising between the second-order intrahepatic bile ducts and the cystic duct. Together with distal and intrahepatic cholangiocarcinoma (dCCA and iCCA; originating distal to, and proximal to this, respectively), gallbladder cancer (GBC) and ampulla of Vater carcinoma (AVC), these clinicopathologically and molecularly distinct entities comprise biliary tract cancer (BTC). Most pCCAs are unresectable at diagnosis, and for those with resectable disease, surgery is extensive, and recurrence is common. Therefore, the majority of patients with pCCA will require systemic treatment for advanced disease. The prognosis with cytotoxic chemotherapy remains poor, driving interest in therapies targeted to the molecular nature of a given patient’s cancer. In recent years, the search for efficacious targeted therapies has been fuelled both by whole-genome and epigenomic studies, looking to uncover the molecular landscape of CCA, and by specifically testing for aberrations where established therapies exist in other indications. This review aims to provide a focus on the current molecular characterisation of pCCA, targeted therapies applicable to pCCA, and future directions in applying personalised medicine to this difficult-to-treat malignancy.

Predicting futility of upfront surgery in perihilar cholangiocarcinoma: Machine learning analytics model to optimize treatment allocation

“…This is critical in discriminating the goodness of a surgical candidate through automatic assessment and progressive learning pruned on experience to select benchmark values, specifically for PHC. [41] This model could be the key to develop an online platform that automatically stratifies patients' risk and improves its performance with each new case added. In the future, these results should be integrated with a learning model predicting individual response to neoadjuvant chemotherapy.…”

“…Comprehensive preoperative strategies mainly encompass optimal biliary decompression and assessment of liver remnant volume and function. Other less standardized fields such as bile replacement strategies to lessen the risk of bacteremia after hepatectomy due to obstructive jaundice, using symbiotics to enhance immune function, assessing nutritional profiles through routine evaluation of the OPNI (Onodera Prognostic Nutritional Index), improving nutritional status through immunonutrition strategies as well as appropriate perioperative selection of antibiotics through bile culture surveillance could represent a turning point in preoperative management of the “futile group.” 40 While preoperative optimization strategies can help lower postoperative morbidity, it is equally important to explore innovative neoadjuvant chemotherapy schemes, particularly those focusing on targeted therapies based on specific molecular subtyping (ie, pembrolizumab for MSI-H, ivosidenib for IDH-1 mutations, and pertuzumab/trastuzumab for HER-2 positivity) that may help reduce the risk of ER 41 . By integrating these measures, the ultimate goal is to categorize patients into a lower surgical risk group, allowing for a safer surgical resection and improved oncological outcomes.…”

“…The application of a machine learning model to a multi-institutional dataset maximizes the number of data available by extrapolating specific trends and learning from them. This is critical in discriminating the goodness of a surgical candidate through automatic assessment and progressive learning pruned on experience to select benchmark values, specifically for PHC 41 . This model could be the key to develop an online platform that automatically stratifies patients’ risk and improves its performance with each new case added.…”

Immune microenvironment of cholangiocarcinoma: Biological concepts and treatment strategies

“…A Phase II clinical trial (NCT03951597) is currently testing gemcitabine in conjunction with PD-1 antibody ICB (JS001), while other clinical trials are investigating nivolumab or pembrolizumab plus Gem+Cis ( 145 ). In the TOPAZ-1 trial, phase III randomized, double-blind, placebo-controlled Gem+Cis combination plus durvalumab (GC-D) was compared with Gem+Cis plus placebo ( 146 ). Based on the recently announced increase in survival with GC-D compared with Gem+Cis alone in TOPAZ-1 trials, ICI-based systemic therapy is expected to be a new first-line treatment option regardless of the TMB and MMR/MSI status ( 147 ).…”

“…Immune-related biomarkers in microenvironment and clinical molecular target in CCA. , placebo-controlled Gem+Cis combination plus durvalumab (GC-D) was compared with Gem+Cis plus placebo(146). Based on the recently announced increase in survival with GC-D compared with Gem+Cis alone in TOPAZ-1 trials, ICI-based systemic therapy is expected to be a new first-line treatment option regardless of the TMB and MMR/MSI status(147).…”