Abstract
The study by Masatoshi Kudo and colleagues 1 Kudo M Moriguchi M Numata K et al. S-1 versus placebo in patients with sorafenib-refractory advanced hepatocellular carcinoma (S-CUBE): a randomised, double-blind, multicentre, phase 3 trial. Lancet Gastroenterol Hepatol. 2017; (published online April 6.)http://dx.doi.org/10.1016/S2468-1253(17)30072-9 Google Scholar published in The Lancet Gastroenterology & Hepatology is an appreciated effort to overcome the unmet needs in treatment of advanced hepatocellular carcinoma. The study is a well-designed, randomised, double-blind, multicentre phase 3 trial comparing S-1 with placebo after progression on or intolerance to sorafenib in Japanese patients with advanced hepatocellular carcinoma. The results unfortunately did not show an improvement in survival with S-1 (11·1 months for S-1 and 11·2 months for placebo) despite encouraging phase 1/2 data (progression-free survival of 3·7 months and overall survival of 16·6 months). 2 Furuse J Okusaka T Kaneko S et al. Phase I/II study of the pharmacokinetics, safety and efficacy of S-1 in patients with advanced hepatocellular carcinoma. Cancer Sci. 2010; 101: 2606-2611 Crossref PubMed Scopus (35) Google Scholar A post-hoc exploratory predictive analysis detected an enriched population with significant benefit (overall survival of 14·0 months for S-1 versus 12·3 months for placebo, p=0·016). These patients had Child-Pugh A cirrhosis, alpha-fetoprotein less than 400 ng/mL, and stage III or IV disease. However, there was no mention of correlation between outcome and prior sorafenib exposure, or if S-1 activity is potentiated by sorafenib-induced tumour necrosis, 3 Itashiki Y Harada K Ferdous T Yoshida H Effects of tumor necrosis factor-related apoptosis-inducing ligand alone and in combination with fluoropyrimidine anticancer agent, S-1, on tumor growth of human oral squamous cell carcinoma xenografts in nude mice. Anticancer Res. 2007; 27: 2365-2375 PubMed Google Scholar although adding S-1 to sorafenib in the first-line setting did not show added benefit compared with historical results with sorafenib alone (overall survival 10·5 months). 4 Ooka Y Chiba T Ogasawara S et al. A phase I/II study of S-1 with sorafenib in patients with advanced hepatocellular carcinoma. Invest New Drugs. 2014; 32: 723-728 Crossref PubMed Scopus (10) Google Scholar S-1 versus placebo in patients with sorafenib-refractory advanced hepatocellular carcinoma (S-CUBE): a randomised, double-blind, multicentre, phase 3 trialS-1 did not prolong overall survival in patients with sorafenib-refractory advanced hepatocellular carcinoma. Further research is needed to identify subgroups of patients who might benefit from S-1. Full-Text PDF
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