TY  - JOUR
A1  - Möhler, Markus
A1  - Maderer, Annett
A1  - Schimanski, Carl C.
A1  - Kanzler, Stephan
A1  - Denzer, Ulrike
A1  - Kolligs, Frank Thomas
A1  - Ebert, Matthias P.
A1  - Distelrath, Andrea
A1  - Geißler, Michael
A1  - Trojan, Jörg
A1  - Schütz, Matthias
A1  - Berie, Lisa
A1  - Sauvigny, Christiane
A1  - Lammert, Frank
A1  - Lohse, Ansgar W.
A1  - Dollinger, Matthias
A1  - Lindig, U.
A1  - Duerr, E. M.
A1  - Lubomierski, Nikolaus
A1  - Zimmermann, S.
A1  - Wachtlin, Daniel
A1  - Kaiser, A.-K.
A1  - Schadmand-Fischer, Simin
A1  - Galle, Peter R.
A1  - Wörns, Marcus Alexander
T1  - 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
T2  - European journal of cancer
N2  - 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.
KW  - Advanced biliary tract cancer
KW  - BTC
KW  - Sorafenib
KW  - Hand-foot syndrome
KW  - VEGFR-2
KW  - VEGFR-3
KW  - c-kit
KW  - PDGFRβ
KW  - Hif1α
Y1  - 2014
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/37370
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-373703
SN  - 0959-8049
N1  - © 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
VL  - 50
IS  - 18
SP  - 3125
EP  - 3135
PB  - Elsevier
CY  - Amsterdam
ER  -