| Background：Hepatocellular carcinoma(HCC)is a common cancer in China．The diseas oftendiagnosed at a late stage when potentially curative therapies are least effective. Forthese patients，medical treatments remain disappointing，and no data shows it isbeneficial for survival． The prognosis for HCC patients who have surgicallyresectable localized tumors is better,but50％of which will have tumor recurrence in2years.Preclinical studies demonstrated that over-expression of vascular endothelialgrowth factor receptor(VEGFR)、platelet-derived growth factor (PDGFR)、Raf／MAPK-ERK kinase (MEK)/extracellular signal regulated kinase (ERK) andphosphatidylinositol-3-OH kinase/Akt/mammalian target of rapamycin (mTOR)cascade play critical roles the development of HCC．Thus，they are potentially themolecular targeted agents for liver cancer therapy．Sorafenib，the first oral multikinase inhibitor,blockstumor cell proliferationby inhibiting Raf／MEK／ERK signaling at the level of Raf kinase，and exerts anantiangiogenic effect by inhibiting vascular endothelial growth factor receptor-2/-3 (VEGFR-2/-3)，and platelet derived growth factor receptor beta (PDGFR-β) tyrosinekinases．It showed that sorafenib prolonged survival time in patients with advancedhepatocellular carcinoma in3phase clinical trials，and its potentialeffect in preventingrecurrence after TACE is prospective．Aimes:To evaluate the prognostic effect and explore the relationship between VEGFand other clinical indicators in combination therapy of transcatheter arterialchemoembolization and Sorafenib on hepatocellular carcinoma through investigatingthe change of serum VEGF. Our research explores predictive targets of combinationtherapy on HCC patients and provide guidence for future clinical treatment.Methods：From December2008to August20l2, two groups of patients with hepatocellularcarcinoma were analyzed and compared，including26patients treated by sorafenibcombined with TACE (therapy group) and the other30patients treated only withTACE(control group)． Serum VEGF level were measured with enzyme-linkedimmunosorbent assay (ELISA) before therapy and other days．The correlation ofclinical and imageology index and serum VEGF level were evaluated before and aftertherapy. The prognostic effect of VEGF and other clinical indicators in combinationtherapy of transcatheter arterial chemoembolization and Sorafenib on hepatocellularcarcinoma were evaluated. To assess the treatment effect based on mRECIST，thetime for progression-free survival (PFS)，overall survival(OS)time and adverse eventswere recorded．Survival rate were analyzed using Kaplan-Meier method and Log-rankanalysis in19.0．Resluts：1.The serum mean concentration of VEGF of all56patiens was448.58±63.46pg/ml pg/ml before treatment. The serum mean concentration of VEGF in the test group and control group were439.97±53.85and456.89±81.65pg/mlrespectively，with no statistical significance.2. The results of Cox correlation showed that the following factors aresignificantly positively related to the elevation of serum VEGF before TACE: multiplehepatoma, tumor well-vascularized, tumor thrombosis in portal vein, distantmetastatic, tumor TNM classification increase and without amicula; The patients haveremaining tumor, new tumor, tumor thrombosis in portal vein and tumorwell-vascularized, their serum VEGF is elevated significantly. The patients have goodlipiodol deposit, their serum VEGF is dropped significantly.3. Till December2012，14patients(53.95％) survived and12patients(includepatients lost to visit) died (46.05％) among the test group，8patients survived(27.53％) and22patients (include patients lost to visit) died (72.46％) among the controlgroup．No complete remission condition was observed in all patients．Among the testgroup, l patient got partial remission,16ones remain stable and9patients gotprogression．While among the control group,conditions remained stable in14patientsand progressed in rest16ones．The disease control rate (DCR) in the test group andcontrol group were65.38％(17/26) and46.67％(14/30) respectively，with nostatistical significance (Χ2=1.975,P=0.160). The median overall survival time (mOS)of test group and control roup were18.5(95％CI:15.5~21.5) months and12.3(95％CI:9.8~14.9) months respectively，and the difference reached statistical significance(Χ2=6.857,P=0.009)．The median time to tumor progression (mTTP) of test group andcontrol group was8.4(95％CI:6.9～9.9) and5.9(95％CI:4.9～6.8) monthsrespectively，and the difierence had statistical significance (Χ2=8.570,P=0.003)．Theadverse events of test group mainly included hand-foot skin reaction，loss of appetite，fever，fatigue and diarrhea. The adverse events of control group mainly included fever,loss of appetite，nausea．vomiting and fatigue. The incidences of hand-foot skinreaction, baldness, diarrhea were significantly higher in test group than those in the control group (P<0.05)．In most patients，these side effects were mild-to-moderate，and alleviated remarkablely after symptomatic treatment.4. Age, gender, pathological classification, the size of tumor and the type oftumor were no statistical difference in test group．VEGF, extrahepatic metastasis, theECOG score, Child-pugh classification, AFP, theportal vein tumor thrombosis andcombined therapy were the prognostic factors in all patients．Lower ECOG Score,AFP and serum VEGF, earlier clinical stage and higher pathological classificationcould indicate better clinical outcome of sorafenib and prognosis of patients．5. Multivariate Cox proportional harzards regression analysis indicated that theECOG scor（eRR=4.832；95%CI为1.463~15.942；P=0.009）, the expression of VEGF（RR=13.370；95%CI为2.802~63.829；P=0.001） and theportal vein tumorthrombosis （RR=2.846；95%CI为1.383~5.857；P=0.005）were independent factorswhich predicted for death．While the factor of Groups (RR=7.920；95%CI为1.845~34.007； P=0.005） was the protective factor with intermediate-advancedhepatocellular carcinoma, Compared with TACE alone, TACE combined withsorafenib can significantly reduce risks of deaths.Conclusions：1．Compared with TACE alone，TACE combined with sorafenib can prolongthe survival of advanced hepatocellular carcinoma.2． ECOG score， groups, extrahepatic metastasis, VEGF, Child-pughclassification, theportal vein tumor thrombosis and AFP level were the prognosticfactors in postoperative HCC patients treated with sorafenib. Lower ECOG Score,AFP and serum VEGF, earlier clinical stage and higher pathological classificationcould indicate better clinical outcome of sorafenib and prognosis of patients．3.VEGF were the prognostic factor in postoperative HCC patients treatedwith sorafenib. Tumor tissue ischemia, hypoxia after TACE resulted in a large number of angiogenic factors such as VEGF secretion. Sorafenib acts predominantly byinhibiting VEGF. TACE combined with sorafenib can prolong the OS and TTPsignificantly for the patients with intermediate-advanced HCC.4．ECOG score, VEGF and theportal vein tumor thrombosis were the riskfactors for survival of postoperative patients treated with sorafenib，increasing scoreof which can weaken sorafenib’effect,thus shorten survival time；and the expressionof VEGF was the protective factor for survival of postoperative patients treated withsorafenib，increasing VEGF which can weaken sorafenib’effect,thus shorten survivaltime too． VEGF may be used as predictive targets of sorafenib’S effect onpostoperative HCC patients．... |
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