| ObjectiveA prospective randomized controlled clinical trial to ShenTaoRuanGan Fang(STYGF) side to side dialectical basic addition and subtraction with sorafenib in combination, to observe its efficacy in patients with advanced primary liver cancer, while the use of internationally recognized quality score amount survival table EORTC QLQ-C30 quality of life for patients with follow-up observation of Shentao soft side and sorafenib combination possible mechanism of initial exploration, while using NCI adverse events criteria for evaluating its safety. Through animal methods, building The tumor model, explore STYGF combine anti-tumor effect of sorafenib and its related mechanism of action that the joint Chinese medicine sorafenib and other targeted therapy of primary HCC provide experimental reference.Methods1. Clinical study section:A prospective randomized controlled trial research methods, in line with the standard set included 60 cases, including 30 cases of Chinese medicine combined group, the control group of 30 patients. Chinese medicine combined group received oral sorafenib 400mg, twice daily, while giving STYGF basic side dialectical decoction orally. The control group received oral sorafenib 400mg, twice daily. Monthly follow-up of patients enrolled to evaluate tumor control, the recording time to disease progression and patient survival time and patient follow-up monitoring of alanine aminotransferase (ALT), total bilirubin (TBIL), albumin (ALB) and other liver function index and serum AFP, VEGF, PDGF levels in patients with liver function evaluation of the situation. And the use of internationally recognized quality of life rating scale EORTC QLQ-C30 quality of life for patients with follow-up study evaluated the quality of life in patients with conditions. Adverse events were evaluated using NCI standard recording adverse events during the study to evaluate drug safety. After the end of the study, performed the statistical analysis of the data processing.2. Experimental study section:Building the HepG2 xenograft model in nude mice, after successful modeling randomly divided into control group, Shen Tao Ruan Gan Fang group, sorafenib and STYGF combine sorafenib, followed by oral administration. Measuring tumor volume and weight of mice every three days during the administration. After treatment, tumor weight measurements taken tumor inhibitory rate was calculated. Western blot was used to detect tumor tissue PI3K, AKT and phosphorylation and expression levels of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) expression, to explore joint STYGF sorafenib inhibitory mechanisms.Results1. Clinical study show:In sorafenib STYGF side group, no patients without tumor objective response rate (ORR) and the control group (13.3% VS 10.0%, P>0.05); and in disease control rate of tumor (DCR), the control group the efficacy of the combination group (66.6% VS 46.6%, P<0.05), prompted sorafenib STYGF not improve objective response rate in patients with liver cancer, but can improve its The disease control rate.The comparison showed that the survival rate of the two groups, in sorafenib STYGF party group, the survival rate of patients 3 months,6 months survival with sorafenib monotherapy group had no significant difference (51.0% VS 46.6%,43.7% VS 34.3%, F>0.05); and 1-year survival rate was found comparing the two groups, one-year survival rate of patients with traditional Chinese medicine combined group than the control group (38.3% VS 21.7%, P<0.05), suggesting that sorafenib STYGF side, does not improve the survival rate of patients with liver cancer recently, but it can be improved 1-year survival rate of patients with long-term.Kaplan-Meier method using two groups of time to disease progression and survival analysis, the results show:time to progression (mTTP) The median sorafenib STYGF HCC patients with sorafenib monotherapy group showed no difference (4.3 months VS 3.6 months, Z=0.858, P=0.354), prompt sorafenib STYGF group than sorafenib monotherapy group, both of which extend in the late no significant difference in terms of time to disease progression in patients with primary liver cancer.Patient survival curves showed that the combined group of patients with liver cancer median survival time (mOS) was 7.7 months, and median sorafenib monotherapy survival time was 6.1 months,1.6 months extension of the combination group compared with the control group, the difference statistically significant (Z=5.998, P=0.014), prompt sorafenib STYGF group sorafenib monotherapy group can improve in advanced primary liver cancer, the median survival time.The group before treatment and after treatment serum AFP level comparisons show that the first serum AFP levels combined group and the control group after treatment than before treatment significantly decreased, the difference was statistically (P<0.05); serum AFP levels between treatment groups the difference between the front and rear (AFP before treatment after treatment difference=AFP-serum AFP serum after treatment) comparison shows that the combined group decreased level of serum AFP levels more significantly than the control group (356.98ng/ml VS 262.44ng/ml, P<0.05). Prompt, after treatment, patients with liver cancer serum AFP average water two significant decline, and the combined group decreased serum AFP level was significantly higher degree.Within the group before treatment and after treatment serum ALT, TBIL and ALB level statistical comparison showed that the serum ALT combination group and the control group after treatment than before treatment and TBIL decreased, the difference was statistically (P<0.05); and two group after treatment than before treatment serum ALB increase, the difference was statistically (P<0.05); prompt, the two groups were not the degree of liver function improved after treatment.Between the two groups before and after treatment serum ALT, TBIL and ALB difference (before and after treatment before treatment difference= value-the value of the absolute values after treatment) comparison shows, ALT and ALB difference between the combined group of patients were higher, the difference Statistics (65.78 VS 37.13,13.43 VS 8.19, P<0.05), while the two groups of patients before and after treatment of TBI difference was no significant difference (P>0.05), prompted a joint group of patients with ALT and the degree of improvement in liver function indicators ALB than the control group, but the two groups did not differ on TBIL of improvements. After treatment, the steady improvement in liver function classification rate of 76.7% and 56.7% respectively, the combined group’s steady improvement in liver function was significantly higher (P<0.05), the degree of improvement in the combination group tips on liver function better the control group, STYGF combine sorafenib increase the protective effect of liver function in patients with liver cancer.The results showed that sorafenib STYGF party group, patients in the functional areas of the score and the score of the overall health of an increase than before treatment, the difference was statistically significant (P<0.05); in symptoms tired fields, nausea and vomiting, shortness of breath, insomnia, loss of appetite, pain, constipation and diarrhea scores than those before treatment decreased significantly (all P<0.05), difficulties in the economic sphere scores than before treatment increased (P<0.05) (Table 11). According to EORTC QLQ-C30 (V3.0) Chinese version of the scoring rules:functional areas and overall health field, the higher the score, indicating better functional status and quality of life; and the symptoms of the field to score higher, indicating more symptoms or problems (worse quality of life), suggesting that the quality of life after treatment, the combined group of patients worsened difficulties in the economic sphere, but in the rest of the field were improved.In the control group, patients with functional areas of the scores and the overall health status scores were more field before treatment increased, the difference was statistically significant (P<0.05); symptoms of shortness of breath in the field, nausea and vomiting, insomnia, pain scores than those before treatment and constipation decreased significantly (all P<0.05), while in fatigue, loss of appetite, diarrhea and economic difficulties in the field of scores than before treatment increased (all P<0.05) (Table 12). According to EORTC QLQ-C30 (V3.0) Chinese version of the scoring rules: prompt treatment to improve the overall quality of life in certain sorafenib monotherapy group, but worsened in fatigue, loss of appetite, diarrhea, and other areas of economic hardship.Patients before and after treatment were compared quality of life score difference (difference= quality of life scores after treatment quality of life score-pre-treatment quality of life score) showed that, in terms of functional areas, the combined group scores in physical and emotional aspects of the superior functionality the control group (P<0.05), while in the role of cognitive and social function score was no significant difference between the two groups (all P>0.05); in the field of symptoms, the combined group in fatigue, nausea and vomiting, shortness of breath, loss of appetite terms of loss and diarrhea scores than the control group (P<0.05), in terms of pain, insomnia, pain and economic hardship fields ratings no significant difference between the two groups (all P>0.05); in the overall health of the field, the combined group’s scores also increased (P<0.05). Tip the quality of life of the whole combination group than after treatment with sorafenib monotherapy group, especially in the physical, emotional and functional areas in fatigue, nausea and vomiting, shortness of breath, loss of appetite and diarrhea in the field, the combined group the degree of improvement of quality of life than the control group.Course of the study, two groups of patients with adverse reactions, such as tables, comparing two groups of adverse reactions occur, the results show that the combined group of hand-foot syndrome, diarrhea, the incidence of fatigue, rash was significantly lower than the control group (both P<0.05), but the two groups were myelosuppression and incidence of adverse reactions was no significant difference (P hypertension> 0.05). Tip sorafenib and STYGF combination, can significantly reduce the sorafenib hand-foot syndrome, diarrhea, fatigue, skin rash and other adverse reactions, but sorafenib bone marrow suppression and hypertension adverse reactions no significant effect occurred.2. The experimental results show:Medicines, sorafenib group and the tumor volume of the combined group were less than the control group (P<0.05), tumor volume less than sorafenib medicine group (P<0.05), and the tumor volume is less than the combined group sorafenib (P<0.05), prompted Shen Tao Ruan Gan Fang on the inhibition of tumor growth has some, but less inhibition of tumor sorafenib, STYGF party applications when combined with sorafenib, sorafenib can enhance tumor inhibition. Comparison of the results of the tumor weight of each group showed Medicines sorafenib group and combined group were less than the control group tumor weight (P<0.05), the inhibition rate sorafenib group than STYGF group (44.5% VS 31.9%, P<0.05), and the inhibitory rate of the combined group in the sorafenib group (68.7%VS 44.5%, P<0.05), prompt STYGF and sorafenib in vivo both have a certain inhibitory effect on liver tumor, which sorafenib tumor inhibition higher than STYGF, while their combination, can be further enhanced inhibition of liver cancer.Western blot analysis showed that normal HepG2 cells in tumor tissue, which PI3K and AKT protein is highly expressed protein PI3K and AKT Medicines sorafenib group and the combined group and phosphorylation levels were varying level decreased (P<0.05), with PI3K and AKT protein expression and phosphorylation of sorafenib STYGF party group the most significant decline (VS. Medicines and sorafenib group, all P<0.05), while no significant difference (all P>0.05) PI3K and AKT protein expression and phosphorylation levels of sorafenib group and Chinese medicine group, suggesting that sorafenib and STYGF can inhibit PI3K, AKT active protein, both of PI3K, AKT inhibition is basically the same, but sorafenib STYGF the application, you can enhance PI3K, AKT protein activity inhibition.Western blot results also show that the normal group of VEGF and PDGF protein is highly expressed protein expression of VEGF and PDGF Medicines sorafenib group and the combination group than those in the control group was significantly decreased (P<0.05), in which the cable sorafenib group expression of VEGF and PDGF were lower than medicine group (P<0.05), while expression of VEGF and PDGF sorafenib STYGF party group the most significant decline (VS. Medicines and cable sorafenib group, all P<0.05), prompted sorafenib and STYGF can inhibit the expression of VEGF and PDGF protein sorafenib VEGF and PDGF inhibitory than STYGF, while their combination, can further enhance the expression of VEGF and PDGF inhibition effect. Conclusion1. STYGF combine sorafenib compared with single-agent sorafenib improve disease control rate in patients with advanced primary liver cancer and improve overall survival.2. STYGF combine sorafenib applications can improve the quality of life in advanced primary liver cancer, the extent of the improvement of quality of life in patients with liver cancer is better than single-agent sorafenib.3. STYGF combine sorafenib in patients with advanced primary liver cancer, the patient may improve liver function, and reduce the incidence of adverse reactions with sorafenib.4. STYGF combine sorafenib applications can enhance the inhibitory effect on tumor growth, which may be related synergistic inhibition of PI3K/AKT signaling pathway and inhibition of VEGF and PDGF and other angiogenesis factor expression related... |
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