How do you treat unresectable, combined hepatocellular/cholangiocarcinoma?

I have historically treated unresectable combined HCC/CCA (CHC) as I have treated unresectable intrahepatic cholangiocarcinomas (IHCCA). I perform Comprehensive Genomic profiling (CGP) upfront in these patients  to investigate the presence of actionable genomic targets. If bulky extrahepatic disease (EHD) is present at diagnosis, I've relied almost entirely on systemic therapy as permitted by end organ function (liver/kidney) and performance status - various combinations of Gemcitabine, flouropyrimidine, platinum and Nab-paclitaxel. In patients with limited EHD, I've utilized various combinations of systemic therapy and liver directed therapy (LDT) after multidisciplinary discussion - dictated by biology of the disease, disease burden, patient performance status and preference.

Even though it has been postulated that CHCs reflect malignant transformation of a common hepatic progenitor cell with divergent differentiation, there is conflicting data emerging about the molecular make-up of CHC (Moeini et al,J Hepatol. 2017 May;66(5):952-961 and Joseph et al, J Pathol. 2019 Jun;248(2):164-178). In short, there is no prospectively validated data to support a specific treatment approach for CHCs and most of us treat these tumors similar to IHCCAs.