M Moehler1, A Maderer2, C Schimanski3, S Kanzler4, U Denzer5, F T Kolligs6, M P Ebert7, A Distelrath8, M Geissler9, J Trojan10, M Schütz2, L Berie2, C Sauvigny2, F Lammert11, A Lohse5, M M Dollinger12, U Lindig13, E M Duerr6, N Lubomierski10, S Zimmermann11, D Wachtlin14, A-K Kaiser14, S Schadmand-Fischer15, P R Galle2, M Woerns2. 1. Department of Internal Medicine, Johannes Gutenberg-University of Mainz, Mainz, Germany. Electronic address: markus.moehler@unimedizin-mainz.de. 2. Department of Internal Medicine, Johannes Gutenberg-University of Mainz, Mainz, Germany. 3. Department of Internal Medicine, Marienhospital Darmstadt, Darmstadt, Germany. 4. 2nd Department of Medicine, Leopoldina Hospital, Schweinfurt, Germany. 5. 1st Department of Medicine, University Hospital Hamburg, Hamburg, Germany. 6. Department of Medicine II, University Hospital Munich, Munich, Germany. 7. 2nd Department of Medicine, University Hospital Mannheim, Mannheim, Germany. 8. Tumor Department, Hospital Fulda, Fulda, Germany. 9. Department of Internal Medicine, Hospital Esslingen, Esslingen, Germany. 10. Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt, Germany. 11. Department of Internal Medicine II, University Hospital Homburg, Homburg, Germany. 12. Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany. 13. Department of Internal Medicine II, University Hospital Jena, Jena, Germany. 14. Interdisciplinary Center for Clinical Trials of the University Medical Center Mainz, Germany. 15. Department of Radiology, Johannes Gutenberg-University of Mainz, Mainz, Germany.
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. 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 withsorafenib (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.
RCT Entities:
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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