pasireotide and Carcinoma--Hepatocellular

Few treatment options are available for patients with advanced or metastatic hepatocellular carcinoma (HCC). Based on preclinical and early clinical efficacy signals and lack of overlapping toxicity, we undertook this multicenter phase II trial to estimate efficacy and safety of everolimus and pasireotide in advanced HCC.. Patients with advanced HCC not amenable to locoregional therapy and Child-Pugh A cirrhosis received everolimus 7.5 mg PO daily and pasireotide LAR 60 mg IM every 28 days. The primary endpoint was time to progression (TTP), with 26 events needed to evaluate if everolimus + pasireotide improved TTP from 2.8 to 4.4 months, with 80% power and an alpha of 0.05. Secondary endpoints included response as measured by RECIST modified for HCC, treatment-emergent adverse events, and overall survival.. After 24 patients were enrolled, results of a randomized trial showing no benefit of everolimus in HCC were released prompting an unplanned interim analysis that found the conditional probability of rejecting the null hypothesis based on events in those patients was 0.08. Therefore accrual was halted. Patients had a median age of 59 years, 21 (88%) had BCLC stage C cancer, and 11 (46%) metastatic disease. Median TTP was 3.5 months (95% CI 2-5.8) and median survival 6.7 months (95% CI 6-infinity). Best response was stable disease in ten patients. Grade 3 hyperglycemia occurred in 6 (25%). There were no grade 4 treatment-emergent events.. Despite promising early efficacy signals, we found no benefit for the combination of everolimus and pasireotide in HCC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Disease-Free Survival; Everolimus; Female; Humans; Liver Neoplasms; Male; Middle Aged; Response Evaluation Criteria in Solid Tumors; Somatostatin

A new non-cytotoxic therapy that SOM230 (pasireotide)，a somatostatin analogue (SSTA) combined with celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor was tested in nude mice bearing HepG2 xenografts. Two agents did not markedly arrest the growth of HepG2 cells but greatly down-regulated vascular endothelial growth factor expression. An imbalance between the vigorous demand and insufficient supply of nutrients and oxygen for tumor growth resulted in the massive necrosis of xenografts. The combination synergistically induced the early apoptosis of HepG2 cells and achieved longest survival without adverse reaction. This impressive strategy appears promising as a systemic therapy for patients with hepatocellular carcinoma (HCC).

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Hepatocellular; Celecoxib; Cell Proliferation; Cyclooxygenase 2 Inhibitors; Down-Regulation; Drug Synergism; Hep G2 Cells; Humans; Liver; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Necrosis; Pyrazoles; Receptors, Somatostatin; Somatostatin; Sulfonamides; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

To investigate the effects of SOM230, a new somatostatin analogue, on the proliferation of hepatocellular carcinoma (HCC) cell line HepG2 in vitro and in vivo, and explore the mechanism underline the necrosis of tumors.. MTT, TdT-mediated dUTP nick end labeling assay (TUNEL) and flow cytometric assay were used to measure the effects of SOM230 on the proliferation and apoptosis of HCC HepG2 cells. Nude mice bearing HCC xenografts of the HepG2 cell line were treated with SOM230 (100 microg/kg/d subcutaneously injection) and saline as a control for eight weeks. The mass and percentage of necrotic volume of the HCC xenografts in nude mice were determined. Western blot was used to detect SSTR2 in HCC xenografts. Immunohistochemical method was used to detect the expression sites of SSTR2 and VEGF in HCC xenografts. ELISA was used to detect the levels of TNFalpha.. No proliferation and apoptosis of HepG2 cells were induced by SOM230 in vitro (F = 0.16, P more than 0.05). The percentage of necrotic volume in SOM230 were significantly higher than that of control group (73.4%+/-7.0% vs 30.2%+/-14.0%, t = -8.02, P more than 0.01). SSTR2 was expressed in blood sinus of HCC xenografts in nude mice. There was no significance difference in the level of SSTR2 expression between SOM230 group and saline treated group. VEGF expression in xenografts was down-regulated by SOM230 treatment. SOM230 treatment did not affect the level of TNFalpha in HCC xenografts (t = -0.24, P more than 0.05).. SOM230 can induce massive necrosis of HCC xenografts only after the blockage of blood flow through down-regulation of VEGF mediated by SSTR2.

Topics: Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Proliferation; Disease Models, Animal; Flow Cytometry; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Humans; Immunohistochemistry; Injections, Subcutaneous; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Random Allocation; Receptors, Somatostatin; Somatostatin; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays