Systemic Treatments with Tyrosine Kinase Inhibitor and Platinum-Based Chemotherapy in Patients with Unresectable or Metastatic Hepatocholangiocarcinoma
Authors: Gigante Elia , Hobeika Christian , Le Bail Brigitte , Paradis Valérie , Tougeron David , Lequoy Marie , Bouattour Mohamed , Blanc Jean-Frederic , Ganne-Carrié Nathalie , Tran Henri , Hollande Clémence , Allaire Manon , Amaddeo Giuliana , Regnault Hélène , Vigneron Paul , Ronot Maxime , Elkrief Laure , Verset Gontran , Trepo Eric , Zaanan Aziz , Ziol Marianne , Ningarhari Massih , Calderaro Julien , Edeline Julien , Nault Jean-Charles 
Published: June 2022

<b><i>Backgrounds and Aims:</i></b> Even if no systemic treatment is currently validated for unresectable hepatocellular-cholangiocarcinoma (cHCC-CCA), tyrosine kinase inhibitors (TKIs) and platinum-based chemotherapy are frequently used in clinical practice. Our study aims to describe the effectiveness of first-line systemic treatments in patients with cHCC-CCA. <b><i>Patients and Methods:</i></b> Patients with histological diagnosis of unresectable or metastatic cHCC-CCA confirmed by a centralized review (WHO classification 2019) and who received systemic treatment from 2009 to 2020 were included retrospectively in 11 centers. The outcomes of patients with cHCC-CCA were compared with patients with hepatocellular carcinoma (HCC) treated by sorafenib (<i>n</i> = 117) and with intrahepatic cholangiocarcinoma (iCCA, <i>n</i> = 94) treated mainly by platinum-based chemotherapy using a frailty Cox model. The efficacy of TKIs and platinum-based chemotherapies in patients with cHCC-CCA was assessed using a doubly robust estimator. <b><i>Results:</i></b> A total of 83 patients with cHCC-CCA were included and were predominantly male (72%) with underlying cirrhosis (55%). 67% of patients had extrahepatic metastases and 31% macrovascular tumor invasion. cHCC-CCAs were more often developed on cirrhosis (55.4%) than iCCA (26.6%) but less frequently than HCC (80.2%) (<i>p</i> &#x3c; 0.001). Both HCC (36.8% and cHCC-CCA (66.2%) had less frequent extrahepatic metastases than iCCA (81%) (<i>p</i> &#x3c; 0.001). Unadjusted overall survival (OS) was better in iCCA (13 months) compared to cHCC-CCA (12 months) and HCC (11 months) (<i>p</i> = 0.130). In multivariable analysis, after adjustment by a Cox frailty model, patients with cHCC-CCA had the same survival as HCC and iCCA (HR = 0.67, 95% CI: 0.37–1.22, <i>p</i> = 0.189 and HR = 0.66, 95% CI: 0.43–1.02, <i>p</i> = 0.064, respectively). ALBI score (HR = 2.15; 95% CI: 1.23–3.76; <i>p</i> = 0.009), ascites (HR = 3.45, 95% CI: 1.31–9.03, <i>p</i> = 0.013), and tobacco use (HR = 2.29, 95% CI: 1.08–4.87, <i>p</i> = 0.032) were independently associated with OS in patients with cHCC-CCA. Among patients with cHCC-CCA, 25 patients treated with TKI were compared with 54 patients who received platinum-based chemotherapies. Patients treated with TKI had a median OS of 8.3 months compared to 11.9 months for patients treated with platinum-based chemotherapy (<i>p</i> = 0.86). After a robust doubly adjustment on tumor number and size, vascular invasion, ALBI, MELD, and cirrhosis, the type of treatment did not impact OS (HR = 0.92, 95% CI: 0.27–3.15, <i>p</i> = 0.88) or progression-free survival (HR = 1.24, 95% CI: 0.44–3.49, <i>p</i> = 0.67). <b><i>Conclusions:</i></b> First-line systemic treatments with TKIs or platinum-based chemotherapies have similar efficacy in patients with unresectable/metastatic cHCC-CCA. The ALBI score predicts OS.