Gemcitabine plus sorafenib versus gemcitabine alone in advanced biliary tract cancer : a double-blind placebo-controlled multicentre phase II AIO study with biomarker and serum programme

  • Background: Since sorafenib has shown activity in different tumour types and gemcitabine regimens improved the outcome for biliary tract cancer (BTC) patients, we evaluated first-line gemcitabine plus sorafenib in a double-blind phase II study. Patients and methods: 102 unresectable or metastatic BTC patients with histologically proven adenocarcinoma of gallbladder or intrahepatic bile ducts, Eastern Cooperative Oncology Group (ECOG) 0–2 were randomised to gemcitabine (1000 mg/m2 once weekly, first 7-weeks + 1-week rest followed by once 3-weeks + 1-week rest) plus sorafenib (400 mg twice daily) or placebo. Treatment continued until progression or unacceptable toxicity. Tumour samples were prospectively stained for sorafenib targets and potential biomarkers. Serum samples (first two cycles) were measured for vascular endothelial growth factors (VEGFs), vascular endothelial growth factor receptor 2 (VEGFR-2) and stromal cell-derived factor 1 (SDF1)α by enzyme-linked immunosorbent assay (ELISA). Results: Gemcitabine plus sorafenib was generally well tolerated. Four and three patients achieved partial responses in the sorafenib and placebo groups, respectively. There was no difference in the primary end-point, median progression-free survival (PFS) for gemcitabine plus sorafenib versus gemcitabine plus placebo (3.0 versus 4.9 months, P = 0.859), and no difference for median overall survival (OS) (8.4 versus 11.2 months, P = 0.775). Patients with liver metastasis after resection of primary BTC survived longer with sorafenib (P = 0.019) compared to placebo. Patients who developed hand-foot syndrome (HFS) showed longer PFS and OS than patients without HFS. Two sorafenib targets, VEGFR-2 and c-kit, were not expressed in BTC samples. VEGFR-3 and Hif1α were associated with lymph node metastases and T stage. Absence of PDGFRβ expression correlated with longer PFS. Conclusion: The addition of sorafenib to gemcitabine did not demonstrate improved efficacy in advanced BTC patients. Biomarker subgroup analysis suggested that some patients might benefit from combined treatment.

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Author:Markus Möhler, Annett Maderer, Carl C. Schimanski, Stephan Kanzler, Ulrike Denzer, Frank Thomas Kolligs, Matthias P. Ebert, Andrea Distelrath, Michael Geißler, Jörg Trojan, Matthias Schütz, Lisa Berie, Christiane Sauvigny, Frank Lammert, Ansgar W. Lohse, Matthias Maximilian Dollinger, U. Lindig, E. M. Duerr, Nikolaus Lubomierski, S. Zimmermann, Daniel Wachtlin, A.-K. Kaiser, Simin Schadmand-Fischer, Peter R. Galle, Marcus Alexander Wörns
Pubmed Id:
Parent Title (English):European journal of cancer
Place of publication:Amsterdam
Document Type:Article
Date of Publication (online):2014/10/15
Date of first Publication:2014/10/15
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Contributing Corporation:Working Group of Internal Oncology (AIO)
Release Date:2015/04/24
Tag:Advanced biliary tract cancer; BTC; Hand-foot syndrome; Hif1α; PDGFRβ; Sorafenib; VEGFR-2; VEGFR-3; c-kit
Page Number:11
First Page:3125
Last Page:3135
© 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung-Nicht kommerziell-Keine Bearbeitung 3.0