Influence of cirrhosis on outcomes of patients with advanced intrahepatic cholangiocarcinoma receiving chemotherapy

Abstract

Background: Cirrhosis is a risk factor for intrahepatic cholangiocarcinoma (iCC). However, its impact on the management of advanced disease is not established. Methods: Retrospective analysis of patients (pts) treated with systemic chemotherapy for advanced iCC in the first-line setting at 2 tertiary cancer referral centers, the second center used to validate findings from the first. Cirrhosis was diagnosed based on at least one element among pathological diagnosis, baseline platelet < 150 G/L, portal hypertension and/or dysmorphic liver at imaging. Results: In the first center (n=185), 55 pts (29.7%) had cirrhosis (74.5 % based on pathological diagnosis). Main aetiology of cirrhosis was alcohol for 17 pts (31%), non-alcoolic steato-hepatitis (NASH) for 10 pts (18.2%), and mixed alcohol and NASH for 9 pts (16.4%). 102 (57.0%) pts received gemcitabine-cisplatin, 55 (30.7%) pts received gemcitabine-oxaliplatin, and 11 (6%) pts received gemcitabine, with no difference between cirrhotic and non-cirrhotic pts (p=0.38). Second-line treatment was less frequent in cirrhotic pts (21.8% vs. 50.0%, p=0.001). Cirrhotic pts experienced more grade 3/4 hematologic toxicity than non-cirrhotic pts (38% vs. 20%, respectively, p=0,014), and more grade 3/4 non-hematologic toxicity (28% vs. 15%, respectively, p=0.048). The overall survival (OS) was significantly shorter in cirrhotic pts; median: 9.0 vs. 13.8 months for non-cirrhotic pts (HR = 1.54 [95%CI: 1.09-2.16]; p = 0.014); confirmed on multivariable analysis, adjusted on ALBI-score, ECOG PS, extension of the disease (liver only disease and bilobar) (HR = 1.53 [95% CI: 1.01-2.33]; p=0.046). However, PFS was not significantly shorter in cirrhotic pts: median 9,9 months vs. 11.7 for non-cirrhotics (p = 0.35). In the second center (n=102), similar results were seen: 27 (26.5%) pts had cirrhosis. The cirrhotic pts experienced more grade 3/4 hematologic toxicities than non-cirrhotic pts (55.6% vs. 25.4%, respectively, p=0.005), and more grade 3/4 non-hematologic toxicity (44.4% vs. 12.7%, respectively, p = 0.001). OS was shorter in cirrhotic pts; median 9.1 months vs. 11.7 months for non-cirrhotic pts (HR = 1.81 [95%CI: 1.14-2.87]; p = 0.011). PFS was not significantly shorter in cirrhotic pts: 7.5 months for patients without cirrhosis, and 4.2 months for pts with cirrhosis (p=0.221). Conclusions: Cirrhosis was frequent in pts with advanced iCC, and had a negative impact on patients’ outcomes, with increased chemotherapy-induced toxicity and shorter OS. Formal assessment and consideration of cirrhosis in the therapeutic management should be recommended and could lead to a dose adjustment.