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

TY - JOUR

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

AU - Moehler, M

AU - Maderer, A

AU - Schimanski, C

AU - Kanzler, S

AU - Denzer, Ulrike

AU - Kolligs, F T

AU - Ebert, M P

AU - Distelrath, A

AU - Geissler, M

AU - Trojan, J

AU - Schütz, M

AU - Berie, L

AU - Sauvigny, C

AU - Lammert, F

AU - Lohse, A

AU - Dollinger, M M

AU - Lindig, U

AU - Duerr, E M

AU - Lubomierski, N

AU - Zimmermann, S

AU - Wachtlin, D

AU - Kaiser, A-K

AU - Schadmand-Fischer, S

AU - Galle, P R

AU - Woerns, M

AU - Working Group of Internal Oncology

AU - Denzer, Ulrike Walburga

N1 - Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

PY - 2014/12/1

Y1 - 2014/12/1

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.

AB - 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 - Adult

KW - Aged

KW - Aged, 80 and over

KW - Antineoplastic Combined Chemotherapy Protocols

KW - Bile Duct Neoplasms

KW - Bile Ducts, Intrahepatic

KW - Biliary Tract Neoplasms

KW - Chemokine CXCL12

KW - Deoxycytidine

KW - Disease-Free Survival

KW - Double-Blind Method

KW - Drug Administration Schedule

KW - Female

KW - Gallbladder Neoplasms

KW - Hand-Foot Syndrome

KW - Humans

KW - Kaplan-Meier Estimate

KW - Male

KW - Middle Aged

KW - Niacinamide

KW - Phenylurea Compounds

KW - Prospective Studies

KW - Quality of Life

KW - Treatment Outcome

KW - Tumor Markers, Biological

KW - Vascular Endothelial Growth Factor Receptor-2

KW - Vascular Endothelial Growth Factors

U2 - 10.1016/j.ejca.2014.09.013

DO - 10.1016/j.ejca.2014.09.013

M3 - SCORING: Journal article

C2 - 25446376

VL - 50

SP - 3125

EP - 3135

JO - EUR J CANCER

JF - EUR J CANCER

SN - 0959-8049

IS - 18

ER -