Another study conducted by Wang et al. combined sorafenib with interferon (IFN)-α, a type I interferon cytokine that activates the JAK-STAT pathway.[38] IFN-α has been commonly used in renal cell carcinoma, melanoma and chronic myelogenous leukemia because it inhibits angiogenesis and tumor cell proliferation. The combination produced a synergistic effect: it decreased HCC cell viability, blocked the progression buy FK506 of the cell cycle, and promoted apoptosis in vitro. In vivo, the combination also inhibited tumor growth and induced apoptosis. The combination of sorafenib and panobinostat is another promising treatment

for HCC. Panobinostat is a drug that inhibits histone deacetylases, which are frequently dysregulated in cancer. When combined with sorafenib, panobinostat decreased cell viability and proliferation, and increased apoptosis and autophagy in vitro.[39] HCC xenografts also had decreased tumor volumes and lived longer when treated with the combination. In a phase II clinical trial, sorafenib was combined with 5-fluorouracil (5-FU) in patients with advanced HCC (www.clinicaltrials.gov, NCT00619541).[40] 5-FU has cytotoxic effects in HCC cells and xenograft models, and it is commonly used to treat gastrointestinal cancers. Thirty-nine patients were given sorafenib at 400 mg b.i.d. and an infusion of 5-FU at 200 mg/sqm/daily from days 1–14 every 3 weeks. The median time

to progression was 8 months, and the median survival learn more time was 13.7 months. The combination was deemed safe, with promising efficacy. Transarterial chemoembolization (TACE) is a common treatment for moderate HCC, and clinical trials aimed to discover if it could be safely combined with sorafenib to produce better outcomes.

TACE can sometimes upregulate VEGF, which can increase HCC growth, invasion and metastasis.[41] In a phase II trial, 50 patients with Barcelona Clinic Liver Cancer stage B or C were treated with sorafenib (median dose, 68.7% of 800 mg daily) 3 days after TACE treatment (www.clinicaltrials.gov, NCT00919009).[41] The overall median time to progression was 7.1 months, and 52% of patients survived at least 6 months. The concurrent treatment these was deemed safe, and the trial promised efficacy. A phase III study analyzed the efficacy of sorafenib when given to Japanese and Korean patients who had already positively responded to TACE treatment.[42] Patients were given either 400 mg of sorafenib b.i.d. or a placebo, and most of the patients began the treatment more than 9 months after TACE. Patients taking sorafenib had a median time to progression of 5.4 months, while those taking the placebo progressed in 3.7 months. The study concluded that sorafenib did not significantly increase the time to progression for patients who had already reaped benefits from TACE. However, low doses of sorafenib and the extended time between sorafenib and TACE treatment may have contributed to this result.