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 PDGFRß 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.

[Single center experience over a 5-year period with sequential transarterial chemoembolization (TACE) in the treatment of hepatocellular carcinoma (HCC)]. / Sequentielle transarterielle Chemoembolisation (TACE) des hepatozellulären Karzinoms (HCC)--Erfahrungsbericht eines einzelnen Zentrums über 5 Jahre.

PURPOSE: To analyze the course of disease of patients treated with sequential TACE and to evaluate the dependent and independent prognostic factors for patient survival using the Cox Proportional Hazard Model. MATERIALS AND METHODS: 94 patients palliatively treated with TACE. Patients were selected if they had been treated at least 3 times. The TACE procedure was carried out at 8-week intervals using a suspension consisting of a fixed dosage of Mitomycin C (10 mg) and 10 ml Lipiodol. Follow-up investigations included contrast-enhanced multislice CT before and after TACE and assessment of the laboratory test results (i. e., blood count, liver enzymes, and coagulation). RESULTS: In 66.7 % of the patients, multifocal tumors were found. In 16.0 % of the patients, the tumor load represented more then 50 % of the liver volume. In 23.4 % of the cases, a portal vein thrombosis was found in the initial CT scan. The mean survival for the total cohort was 24.1 months (95 %-CI 20.1 - 28.2). During the investigation period, 72/94 of the patients died. The cumulative 1-year, 2-year, and 3-year survival rates are 71.6 %, 33.9 %, und 17.2 %, respectively. A median of 6.0 +/- 3.1 (range 14, n total = 612 TACE) was performed in each patient. A total of 62.5 % patients died because of tumor progression whereas 18.1 % died due to progressive liver failure. Patients in whom the tumor responded to the TACE treatment and who did not develop ascites or those with Okuda stage I or unifocal tumor growth showed a survival benefit whereas the presence of portal vein thrombosis was associated with a significantly poor outcome (p < 0.05). The Child-Pugh stage was not statistically significant for the disease course; the occurrence of new tumor lesions had no influence with regard to 1-year and 2-year survival but had a significant influence on long-term survival (p < 0.05). Independent prognostic factors are (multivariate analysis; p < 0.05): number of TACE performed, tumor type (i. e., unifocal vs. multifocal), response to TACE (response vs. progression), and Okuda stage. CONCLUSION: Our results emphasize the value of TACE in the palliative treatment of HCC. Under sequential TACE therapy the course of disease in patients suffering from portal vein thrombosis was not significantly worse. Crucial prognostic factors for the course of the HCC are tumor type and extension, response to TACE, and liver function at the beginning of TACE.