Early Clinical Response after 2 Weeks of Sorafenib Therapy Predicts Outcomes and Anti-Tumor Response in Patients with Advanced Hepatocellular Carcinoma

Abstract

Background & AimsWe evaluated the relationship between the early clinical response after 2 weeks of sorafenib therapy and the outcomes and anti-tumor response in patients with advanced hepatocellular carcinoma.MethodsFifty-seven patients who had intrahepatic hypervascular hepatocellular carcinoma and Child-Pugh (CP) class A disease at baseline were enrolled in this prospective, multicenter, observational, non-interventional study. As an early clinical response after 2 weeks of sorafenib therapy, changes in intra-tumor blood flow on contrast-enhanced computed tomography (CE-CT), alpha-fetoprotein (AFP) levels, and remnant liver function were investigated.ResultsAfter 2 weeks of sorafenib therapy, there were 26 patients (45.6%) without disappearance of arterial tumor enhancement on CE-CT, 15 patients (26.3%) with an AFP ratio of >1.2, and seven patients (12.3%) with two or more increments in the CP score. Multivariate analysis showed that the absence of disappearance of arterial tumor enhancement on CE-CT, AFP ratio of >1.2, and two or more increments in the CP score after 2 weeks of sorafenib therapy were significant and independent predictors of worse survival. Upon scoring these three variables as "poor prognostic factors", patients with poor prognostic score 4, 3 or 2 (n = 17) had significantly worse outcomes and a significantly higher progressive disease (PD) rate based on modified Response Evaluation Criteria in Solid Tumors at 6 weeks after sorafenib therapy than those with poor prognostic score 1 or 0 (n = 40) (median overall survival: 194 days vs. 378 days; p = 0.0010, PD rate: 70.6% vs. 20.0%; p = 0.0003, respectively).ConclusionsChanges in intra-tumor blood flow on CE-CT, AFP levels, and remnant liver function after 2 weeks of sorafenib therapy may be useful for predicting the outcomes and anti-tumor response to sorafenib in patients with advanced hepatocellular carcinoma.

Fever within 2 Weeks of Sorafenib Therapy Predicts Favorable Treatment Efficacy in Patients with Advanced Hepatocellular Carcinoma

“…Disappearance of intratumor blood flow is often observed after sorafenib therapy and might be a marker of good antitumor efficiency [9,13]. In our previous study [9], we reported that the disappearance of arterial tumor enhancement on CE-CT after 2 weeks of sorafenib therapy was a significant predictor of better survival.…”

“…The starting dose of sorafenib (Nexavar; Bayer Yakuhin, Ltd., Osaka, Japan) was 800 mg/day administered orally. However, out of concern for the possibility of having to discontinue sorafenib treatment at an early stage due to adverse events, the initial dose was set at 400 mg/day for patients who were 80 years or older, for those who had a body weight of 50 kg or less, for those with poor renal function, and for those who had a history of treatment for varices or ascites [8,9]. In the case of the occurrence of drug-related adverse events, a dose reduction or temporary interruption was maintained until symptoms resolved to grade 1 or 2 according to the guidelines provided by the manufacturer.…”

“…Four-phase (i.e., unenhanced, late arterial, portal venous, and equilibrium phase) CE-CT examination was obtained at baseline, at 2 and 6 weeks after sorafenib administration, and every 4-8 weeks thereafter [9]. Antitumor response was evaluated according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) [10].…”

“…Disappearance of intratumor blood flow was defined as tumor staining in at least one target lesion that showed a disappearance of arterial tumor enhancement at 2 weeks after dose when compared with staining on CE-CT at baseline [9]. With regard to intratumor blood on CE-CT at 2 weeks after sorafenib administration, patients were classified into the following two groups: (1) patients whose intratumor blood flow disappeared (the DA group) and (2) patients whose intratumor blood flow did not disappear (the non-DA group) at 2 weeks after the start of sorafenib therapy.…”

Synthesis of 4-Chloro-N, N-Dimethyl Pyridine Car Box Amide

“…The incidence of liver cancer is about 20/10000, due to early symptoms of liver cancer is not obvious [1], nearly 80% of patients is already advanced, half of the world's liver cancer occurred in China, and in China the primary factor in liver cancer Among them, hepatitis B in the first place [2][3][4][5], the causative factor with liver cancer in Europe and the United States are very different.4-Chloro-N, N-dimethyl pyridine car box amide is part of the key intermediate in sorafenib, and largely affects the activity of sorafenib, which is a novel multi-targeted oral drug for the treatment of tumors and Sorafenib is a new multi-target anti-tumor drugs [6][7][8][9][10], developed by the German Bayer Pharmaceutical Company, which can act on both tumor cells and tumor blood vessels. It has a dual antitumor effect by inhibiting RAF / MEK / ERK-mediated cell signaling pathways directly by inhibiting tumor cell proliferation [11][12], But also by blocking angiogenin and platelet-derived growth factor receptor block tumor neovascularization formation, and indirectly inhibit tumor cell growth.…”