S-1 doses up to 80В mg/m 2/day can be used as a single therapeutic agent or 35 to 60В mg/m 2/day when combined with other cytotoxic agents in phase I/II studies. The pharmacology, pharmacokinetics (PK), and toxicology of S-1 have been studied in a variety of animal models 11, 12, 13 and its efficacy and tolerability have been shown in advanced cancers of digestive system in clinical trials 14, 15, 16. S-1 was developed to enhance the clinical advantage of oral fluoropyrimidine and ameliorate the disadvantage of gastrointestinal toxicity 10. S-1 is a new oral pyrimidine fluoride-derived anticancer agent that consists of tegafur and 2 classes of modulators, gimeracil (CDHP, ) and oteracil potassium (Oxo, ). However, the mechanisms underlying this synergistic effect between anti-angiogenetic and chemotherapeutic agents remain elusive 2. This approach has been supported by several recently published randomized studies, which showed that adding bevacizumab to conventional cytotoxic agents improves treatment results in colorectal cancer patients. To further improve the antitumor effect of antiangiogenesis agents, several strategies have been proposed, including a combination of antiangiogenesis agents with conventional cytotoxic chemotherapy. Sorafenib (400В mg twice daily) was approved by the Food and Drug Administration in the US for the treatment of advanced renal cell carcinoma in Dec 2005, unresectable hepatocellular carcinoma in Nov 2007, and progressive advanced differentiated thyroid cancer refractory to radioiodine treatment in Nov 2013 9. The dosage and toxicity of sorafenib have been evaluated in phase I studies for cancer patients 7, 8. Its antitumor effect has also been confirmed in a variety of human cancer cell lines in vitro and in vivo 6. In an in vitro kinase assay, sorafenib had an inhibitory effect on multiple kinases, including c-Raf, wild type B-Raf, mutant B-Raf, and VEGFR-2, etc 5. Sorafenib, a novel bi-aryl urea, is a potent inhibitor of Raf kinase and VEGF receptor-2 (VEGFR2). sunitinib and sorafenib), have either been used alone or in combination with chemotherapy to treat various cancers 2, 3, 4.

Agents targeting VEGF, including VEGF antibody, bevacizumab, and VEGF receptor tyrosine kinase inhibitors (e.g. Furthermore, it affects the function of immune cells in the tumor microenvironment and can promote the growth, survival, migration, and invasion of cancer cells 1. Vascular endothelial growth factor (VEGF) is involved in angiogenesis and vascular permeability in cancers. This result warrants further phase II studies for advanced pNET and colon cancer to evaluate the efficacy of this combination. This study determined the recommended (MTD) S-1 dose of 30В mg/m 2 bid for this regimen. Four colon cancer patients had stable disease and 3 of them had progression-free survival greater than 6В months.

One pancreatic neuroendocrine tumor (pNET) patient achieved a durable partial response (27.9В months). DLT developed in two (one grade 3 erythema and one prolonged grade 2 hand-foot-skin reaction) of the 6 patients at 35В mg/m 2 dose level. Thirteen patients were enrolled between May 2010 and Feb 2012. Eligible patients received escalating doses (30, 35, and 40В mg/m 2 bid) of S-1 Day 1 (D1)вЂ“D14 and continuous sorafenib 400В mg bid from cycle 1 D8 every 21В days in a standard 3вЂ‰+вЂ‰3 study design. We conducted a phase I dose escalation study to determine dose-limiting toxicity (DLT) and maximal tolerated dose (MTD) of S-1 when combined with sorafenib for refractory solid tumors.

Sorafenib, an oral multikinase inhibitor, was found to prolong the survival of various cancers and enhance the cytotoxicity of chemotherapeutic agents. S-1, an oral pyrimidine fluoride-derived agent, is effective against various cancers.

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