title: 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.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Internal Medicine, Johannes Gutenberg-University of Mainz, Mainz, Germany. Electronic address: markus.moehler@unimedizin-mainz.de.
authors.forename: M
authors.initials: M
authors.lastname: Moehler
authors.affiliation: Department of Internal Medicine, Johannes Gutenberg-University of Mainz, Mainz, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Maderer
authors.affiliation: Department of Internal Medicine, Marienhospital Darmstadt, Darmstadt, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Schimanski
authors.affiliation: 2nd Department of Medicine, Leopoldina Hospital, Schweinfurt, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Kanzler
authors.affiliation: 1st Department of Medicine, University Hospital Hamburg, Hamburg, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Denzer
authors.affiliation: Department of Medicine II, University Hospital Munich, Munich, Germany.
authors.forename: F T
authors.initials: FT
authors.lastname: Kolligs
authors.affiliation: 2nd Department of Medicine, University Hospital Mannheim, Mannheim, Germany.
authors.forename: M P
authors.initials: MP
authors.lastname: Ebert
authors.affiliation: Tumor Department, Hospital Fulda, Fulda, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Distelrath
authors.affiliation: Department of Internal Medicine, Hospital Esslingen, Esslingen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Geissler
authors.affiliation: Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Trojan
authors.affiliation: Department of Internal Medicine, Johannes Gutenberg-University of Mainz, Mainz, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schütz
authors.affiliation: Department of Internal Medicine, Johannes Gutenberg-University of Mainz, Mainz, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Berie
authors.affiliation: Department of Internal Medicine, Johannes Gutenberg-University of Mainz, Mainz, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Sauvigny
authors.affiliation: Department of Internal Medicine II, University Hospital Homburg, Homburg, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Lammert
authors.affiliation: 1st Department of Medicine, University Hospital Hamburg, Hamburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Lohse
authors.affiliation: Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany.
authors.forename: M M
authors.initials: MM
authors.lastname: Dollinger
authors.affiliation: Department of Internal Medicine II, University Hospital Jena, Jena, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Lindig
authors.affiliation: Department of Medicine II, University Hospital Munich, Munich, Germany.
authors.forename: E M
authors.initials: EM
authors.lastname: Duerr
authors.affiliation: Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Lubomierski
authors.affiliation: Department of Internal Medicine II, University Hospital Homburg, Homburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Zimmermann
authors.affiliation: Interdisciplinary Center for Clinical Trials of the University Medical Center Mainz, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Wachtlin
authors.affiliation: Interdisciplinary Center for Clinical Trials of the University Medical Center Mainz, Germany.
authors.forename: A-K
authors.initials: AK
authors.lastname: Kaiser
authors.affiliation: Department of Radiology, Johannes Gutenberg-University of Mainz, Mainz, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Schadmand-Fischer
authors.affiliation: Department of Internal Medicine, Johannes Gutenberg-University of Mainz, Mainz, Germany.
authors.forename: P R
authors.initials: PR
authors.lastname: Galle
authors.affiliation: Department of Internal Medicine, Johannes Gutenberg-University of Mainz, Mainz, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Woerns
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001650:Bile Duct Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001653:Bile Ducts, Intrahepatic; D001661:Biliary Tract Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014408:Biomarkers, Tumor / Q000378:metabolism*; D054377:Chemokine CXCL12 / Q000378:metabolism; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005706:Gallbladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D060831:Hand-Foot Syndrome / Q000209:etiology; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects; D011446:Prospective Studies; D011788:Quality of Life; D000077157:Sorafenib; D016896:Treatment Outcome; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D042442:Vascular Endothelial Growth Factors / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D014408:Biomarkers, Tumor; D054377:Chemokine CXCL12; D010671:Phenylurea Compounds; D042442:Vascular Endothelial Growth Factors; D003841:Deoxycytidine; D009536:Niacinamide; D000077157:Sorafenib; D040301:Vascular Endothelial Growth Factor Receptor-2; D000093542:Gemcitabine
keywords: Advanced biliary tract cancer; BTC; Hand-foot syndrome; Hif1α; PDGFRβ; Sorafenib; VEGFR-2; VEGFR-3; c-kit