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Sorafenib (Nexavar) may improve progression-free survival (PFS) and overall survival (OS) of advanced hepatocellular carcinoma (HCC). Xiong, Y. Q. et al. Human hepatocellular carcinoma tumor-derived endothelial cells manifest increased angiogenesis capability and drug resistance compared with normal endothelial cells. Sorafenib is currently regarded as the only effective chemotherapy regimen for advanced HCC 27 , but the overall survival after this treatment remains limited due to the frequent development of resistance to sorafenib 28 In general, sorafenib resistance includes HCC cell resistance and microenvironmental resistance.
Sorafenib resistance is one of the main obstacles to the treatment of advanced/recurrent hepatocellular carcinoma (HCC). REFLECT was a large (N=954) Phase III, randomized, multicenter, open-label trial conducted by Eisai to compare the efficacy and safety of lenvatinib versus sorafenib as a first-line systemic treatment in patients with unresectable hepatocellular carcinoma (HCC). Bruix J, Merle P, Granito A, et al. Hand-foot skin reaction (HFSR) and overall survival (OS) in the phase 3 RESORCE trial of regorafenib for treatment of hepatocellular carcinoma (HCC) progressing on sorafenib.
Both of the above mechanisms are targets for a new class of immune checkpoint inhibitors, either through interruption of the interaction between PD-1 and PD-L1 or between CTLA-4 and B7. By interfering with cancer's ability to ensure immune cell quiescence, these drugs can induce powerful immune responses to a diverse number of cancer, including melanoma, renal cell carcinoma, non-small cell lung cancers, and head and neck cancers ( 27 - 33 ). In fact, a number of these agents have shown significant promise in the treatment of advanced HCC. In the United States, HCC is the fifth leading cause of cancer-related deaths ( 1 , 2 ). Even with advances in therapy, HCC still confers significant mortality, with 5-year survival rates of only 18% from 2005 to 2011 ( 2 ). In its early stages, surgery and liver transplantation are a potentially curative treatment ( 3 ). However, up to 80% of patients present at an incurable stage ( 4 ). In such situations, local therapies including transarterial chemoembolization (TACE) are often used to control the disease when HCC is confined to the liver. Keywords: Hepatocellular carcinoma (HCC); sorafenib; systemic therapy; immunotherapy; clinical trials; tyrosine kinase inhibitors.
Preliminary results from a phase II, randomized, double-blind study of sorafenib plus doxorubicin versus placebo plus doxorubicin in patients with advanced hepatocellular carcinoma. The only therapy shown to significantly improve overall survival in patients with liver cancer, it was approved in Europe for the treatment of HCC last month. As reported previously, MMPs degrade the basement membrane and extra cellular matrix, and thereby create space for cell migration and invasion ( 31 ). MMPs also participate in maturation and liberation of substantial growth factors ( 32 ). In hepatocellular carcinoma cells, sorafenib has been reported to inhibit migration and invasion through suppression of MMPs expression ( 23 ). Specifically, MMP-2 and MMP-9 inhibitor, termed 5a, has been proven to enhance apoptosis in cancer cells ( 33 ). Chen et al. ( 34 ) demonstrated AKT/mTOR pathway was associated with invasion and metastasis of hepatocellular carcinoma through MMP-9.
In our study, we interestingly found that IL-27 or sorafenib could inhibit cell proliferation, migration and invasion while promoted cell apoptosis of bladder cancer cells, and the combination of these two drugs significantly augmented the influence in HTB-9 cells. The number of apoptotic cells was further increased by the drug combination (P<0.001 compared to control), resulting in a significant difference compared to single treatment of IL-27 (P<0.001) or sorafenib (P<0.01). The multi-kinase inhibitor (MKI) sorafenib can be an effective palliative therapy for patients with hepatocellular carcinoma (HCC).
The adoption of sorafenib into oncology practice as a first-line systemic treatment for advanced hepatocellular carcinoma (HCC) is not well understood. Currently, sorafenib plays a critical role in treating patients with advanced stage HCC, contributing to an improved overall survival in treated patients in clinical trials 12 , 13 Unfortunately, some patients don't benefit from the treatment. Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide, with an increasing incidence in the United States and China 1 , 2 In China, HCC commonly arises in patients with chronic liver diseases.
Liu J, Liu Y, Meng L, Ji B, Yang D. Synergistic Antitumor Effect of Sorafenib in Combination with ATM Inhibitor in Hepatocellular Carcinoma Cells.