Pattern of progression of intrahepatic cholangiocarcinoma: Implications for second-line clinical trials.

Background Intrahepatic cholangiocarcinoma (iCCA) is the second most frequent liver cancer. The overall survival of iCCA and other biliary tract cancers (BTC) remain poor. Recently, the ABC-06 trial reported the superiority of FOLFOX vs clinical observation as a second line treatment. Still, survival benefit was less than expected. We hypothesized that the pattern of progression of iCCA can drive post progression survival (PPS), similarly to hepatocellular carcinoma. Methods Multicenter retrospective evaluation of consecutive iCCA patients who progressed after a frontline systemic treatment with gemcitabine as monotherapy, or in combination with platinum. Radiological assessment of progression was evaluated according to RECIST 1.1. The progression pattern was divided according to the presence/absence of new extrahepatic lesions (NEH). Results We included 206 patients from 5 centers. The median OS was 14.1 months and its independent predictors (hazard ratio [HR], 95% confidence interval [CI]) were: previous surgery 0.699 [0.509-0.961], performance status>0 2.445 [1.788-3.344], permanent first line discontinuation 16.072 [5.102-50.633], registration of ascites 2.226 [1.448-3.420] or bilirubin>3mg/dl 3.004 [1.935-4.664] during the follow-up, and disease progression 2.523 [1.261-5.050]. The appearance of NEH independent predicted OS 2.18 [1.55-3.06] in patients with radiological progression. Amongst 138 patients eligible for a second-line treatment, PPS was 16.8 and 5.9 months in cases without and with NEH, respectively (p=0.001). Progression due to NEH lesions was an independent predictors of PPS 1.873[1.333-2.662], together with performance status, time-to-progression to the frontline treatment, bilirubin>3mg/dl, and ascites. Conclusions PPS of iCCA is influenced by progression pattern, with important implications for second-line trial design and analysis.