参桃软肝方联合索拉非尼治疗中晚期原发性肝癌的临床研究及机制探讨
发布时间：2018-08-31 14:56
【摘要】：目的：采用前瞻性随机对照临床研究方法,以参桃软肝方为基本方辨证加减与索拉非尼联合应用,观察其对中晚期原发性肝癌的疗效,同时采用国际公认的生存质量评分量表EORTC QLQ-C30对患者生存质量进行随访观察评价其对患者生存质量的影响,采用NCI不良反应事件标准评价其安全性。通过动物实验方法,构建裸鼠肝癌移植瘤模型,探索参桃软肝方联合索拉非尼的抑瘤作用及其相关的作用机制,以为中医药联合索拉非尼等靶向药物治疗原发性肝癌提供一定的实验参考依据。方法：1.临床研究部分：采用前瞻性随机对照试验研究方法,纳入符合入组标准病例60例,其中中药联合组30例,对照组30例。中药联合组给予口服索拉非尼400mg,每日2次,同时给予参桃软肝方为基本方的辨证中药汤剂口服。对照组给予口服索拉非尼400mg,每日2次。每月对入组患者进行随访,评价肿瘤控制情况,记录患者疾病进展时间及生存时间,同时随访监测患者谷丙转氨酶(ALT)、总胆红素(TβIL)、白蛋白(ALB)等肝功能指标,评价患者肝功能分级情况。并采用国际公认的生存质量评分量表EORTC QLQ-C30对患者生存质量进行随访观察评价患者生存质量情况。采用NCI不良反应事件评价标准记录研究过程中发生的不良反应,以评价药物安全性。2.实验研究部分：构建裸鼠HepG2肝癌移植瘤模型,造模成功后随机分为对照组、参桃软肝方组、索拉非尼组和参桃软肝方联合索拉非尼组,然后进行灌胃给药。给药期间每3天测量瘤体体积和小鼠体重。给药结束后,取瘤体测量瘤重,计算抑瘤率。应用Western blot方法检测瘤体组织PI3K、AKT及其磷酸化表达水平以及检测血管内皮生长因子(VEGF)和血小板源性生长因子(PDGF)表达,以探索参桃软肝方联合索拉非尼的抑瘤机制。结果：1.临床研究结果显示,在索拉非尼联合参桃软肝方组中,患者的肿瘤客观缓解率(ORR)与对照组无明显无差异(13.3% VS 10.0%,P0.05)；而在肿瘤的疾病控制率(DCR)方面,联合组的疗效高于对照组(66.6% VS 46.6%,P0.05),提示索拉非尼联合参桃软肝方,不能提高对肝癌患者的客观缓解率,但可提高其疾病控制率。两组的生存率比较结果显示,在索拉非尼联合参桃软肝方组中,患者的3个月生存率、6个月生存率与索拉非尼单药组无明显差异(51.0% VS 46.6%,43.7% VS 34.3%,均P0.05)；而对比两组1年生存率发现,中药联合组患者的1年生存率优于对照组(38.3% VS 21.7%,P0.05),提示索拉非尼联合参桃软肝方,不能提高肝癌患者的的近期生存率,但可以提高患者远期的1年生存率。采用Kaplan-Meier方法对两组的疾病进展时间和生存时间进行分析,结果显示：索拉非尼联合参桃软肝方组肝癌患者的中位疾病进展时间(mTTP)与索拉非尼单药组相比无差异(4.3个月VS 3.6个月,Z=0.858,P=0.354),提示索拉非尼联合参桃软肝方组较索拉非尼单药组,两者在延长中晚期原发性肝癌患者的疾病进展时间方面无明显差别。患者生存曲线显示,联合组肝癌患者中位生存时间(mOS)为7.7个月,索拉非尼单药组的中位生存时间为6.1个月,联合组较对照组延长1.6个月,差异有统计学意义(Z=5.998,P=0.014),提示索拉非尼联合参桃软肝方组对比较索拉非尼单药组可以提高中晚期原发性肝癌患者的中位生存时间。组内治疗前与治疗后的血清AFP水平比较显示,联合组和对照组治疗后的血清AFP水平均较治疗前明显下降,差异具有统计学(P0.01)；两组间的血清AFP水平治疗前后差值(AFP治疗前后差值=治疗前血清AFP-治疗后血清AFP)比较显示,联合组血清AFP水平的下降程度较对照组更明显(359.83ng/ml VS 266.23ng/ml, P0.05)。提示,经治疗后,两组肝癌患者的血清AFP水平均出现明显下降,且联合组血清AFP水平的下降程度明显高于对照组。组内治疗前与治疗后血清ALT、TBIL及ALB水平统计学比较显示,联合组和对照组治疗后的血清ALT和TBIL均较治疗前明显下降,差异具有统计学(P0.05)；而两组治疗后的血清ALB均较治疗前提高,差异具有统计学(P0.05)；提示,治疗后两组的肝功能均有不程度的好转。两组间治疗前后血清ALT、TBIL及ALB差值(治疗前后差值=治疗前数值-治疗后数值的绝对值)比较显示,联合组患者ALT和ALB的差值均高于对照组,差异具有统计学(P0.05),而两组患者的TBI治疗前后差值无明显差异(P0.05),提示联合组对患者ALT和ALB等肝功能指标的改善程度优于对照组,而对TBIL的改善方面两组无差异。治疗后两组肝功能分级的稳定好转率分别为76.7%和56.7%,联合组肝功能分级的稳定好转率明显高于对照组(P0.05),提示联合组对肝功能的改善程度优于对照组,参桃软肝方联合索拉非尼可增加对肝癌患者肝功能的保护作用。研究结果显示,在索拉非尼联合参桃软肝方组中,患者在功能领域各项评分及总体健康状况领域评分较治疗前增加,差异具有统计学意义(均P0.05)；在症状领域的疲倦、恶心与呕吐、气促、失眠、食欲丧失、疼痛、便秘和腹泻评分均较治疗前减少,差异显著(均P0.05),在经济困难领域评分较治疗前升高(P0.05)(见表11)。依据EORTC QLQ-C30(V3.0)中文版计分规则：功能领域和总体健康状况领域得分越高,说明功能状况和生命质量越好；而症状领域得分越高,表明症状或问题越多(生命质量越差),提示治疗后联合用药组患者的生存质量在经济困难领域出现恶化,而在其余各项领域均得到改善。在对照组中,患者功能领域各项评分及总体健康状况领域评分均亦较治疗前增加,差异具有统计学意义(均P0.05)；在症状领域的气促、恶心与呕吐、失眠、疼痛和便秘评分均较治疗前减少,差异显著(均P0.05),而在疲倦、食欲丧失、腹泻和经济困难领域的评分均较治疗前增加(均P0.05)(见表12)。依据EORTC QLQ-C30(V3.0)中文版计分规则：提示治疗后索拉非尼单药组的生存质量总体上有一定提高,但在疲倦、食欲丧失、腹泻和经济困难等领域出现恶化。比较两组患者治疗前后生存质量评分差值(生存质量评分差值=治疗后生存质量评分-治疗前生存质量评分)结果显示,在功能领域方面,联合组在躯体和情绪功能方面的评分优于对照组(均P0.05),而在角色、认知和社会功能方面的评分两组无明显差异(均P0.05)；在症状领域,联合组在疲倦、恶心与呕吐、气促、食欲丧失和腹泻方面的评分优于对照组(均P0.05),在便秘、失眠、疼痛和经济困难领域等方面的评分两组间无明显差异(均P0.05)；在总体健康状况领域,联合用药组的评分亦高于对照组(均P0.05)。提示治疗后联合用药组的生存质量总体上优于索拉非尼单药组,尤其在躯体、情绪功能领域以及在疲倦、恶心与呕吐、气促、食欲丧失和腹泻等症状领域中,联合组对生存质量的改善程度优于对照组。研究过程中,两组患者发生的不良反应情况如表,对比两组不良反应的发生情况,结果显示,联合用药组的手足综合征、腹泻、疲劳、皮疹的发生率明显低于对照组(均P0.05),而两组患者骨髓抑制和高血压不良反应发生率无明显差异(均P0.05)。提示索拉非尼与参桃软肝方联合应用,可明显降低索拉非尼的手足综合征、腹泻、疲劳、皮疹等不良反应的发生,但对索拉非尼骨髓抑制和高血压不良反应的发生无明显影响。2.实验研究结果显示：中药组,索拉非尼组以及联合组的瘤体体积均小于对照组(均P0.05),索拉非尼组的瘤体体积小于中药组(P0.05),而联合组的瘤体体积小于索拉非尼组(P0.05),提示参桃软肝方对肿瘤的生长有一定抑制作用,但其对肿瘤的抑制作用不及索拉非尼,参桃软肝方联合索拉非尼应用时,可增强索拉非尼的肿瘤抑制作用。各组瘤重的比较结果显示,中药组,索拉非尼组以及联合组的瘤重均小于对照组(P0.05),索拉非尼组的抑瘤率优于参桃软肝方组(44.5% VS 31.9%,P0.05),而联合组的抑瘤率高于索拉非尼组(68.7% VS 44.5%,P0.05),提示参桃软肝方和索拉非尼体内均对肝癌瘤体有一定抑制作用,其中索拉非尼对肿瘤的抑制作用高于参桃软肝方,而两者联合应用时,可进一步增强对肝癌的抑制作用。Western blot结果显示,正常的肝癌HepG2细胞瘤体组织中,其PI3K和AKT蛋白呈高表达,而中药组,索拉非尼组以及联合组的PI3K和AKT蛋白表达及其磷酸化水平均出现不同程度下降(均P0.05),以索拉非尼联合参桃软肝方组的PI3K和AKT蛋白表达及其磷酸化水平下降最明显(VS.中药组和索拉非尼组,均P0.05),而索拉非尼组与中药组的PI3K和AKT蛋白表达及其磷酸化水平无明显差异(均P0.05),提示索拉非尼和参桃软肝方均可抑制PI3K、AKT蛋白的活性,两者对PI3K、AKT的抑制作用基本相同,而索拉非尼联合参桃软肝方应用时,可增强对PI3K、AKT蛋白活性的抑制作用。Western blot结果还显示,正常组的VEGF和PDGF蛋白呈高表达,而中药组,索拉非尼组以及联合组的VEGF和PDGF蛋白表达均较正常组明显下降(均P0.05),其中索拉非尼组中VEGF和PDGF的表达均低于中药组(均P0.05),而索拉非尼联合参桃软肝方组的VEGF和PDGF蛋白表达下降最明显(VS.中药组和索拉非尼组,均P0.05),提示索拉非尼和参桃软肝方均可抑制VEGF和PDGF蛋白的表达,索拉非尼对VEGF和PDGF的抑制作用优于参桃软肝方,而两者联合应用时,可进一步增强对VEGF和PDGF蛋白表达的抑制作用。结论：1.参桃软肝方联合索拉非尼较单药索拉非尼可提高中晚期原发性肝癌患者的疾病控制率,延长患者生存时间。2.参桃软肝方联合索拉非尼应用可改善中晚期原发性肝癌患者生存质量,其对肝癌患者生存质量的改善程度优于单药索拉非尼。3.参桃软肝方联合索拉非尼治疗中晚期原发性肝癌患者时,可改善患者肝功能情况,并可降低索拉非尼不良反应的发生。4.参桃软肝方联合索拉非尼应用,可增强对肝癌瘤体生长的抑制作用,其机制可能与其协同抑制PI3K/AKT信号通路以及抑制VEGF和PDGF等肿瘤新生血管生成因子的表达有关。
[Abstract]:Objective: To observe the curative effect of Shentao Ruangan Prescription combined with sorafenib on advanced primary hepatocellular carcinoma by prospective randomized controlled clinical research method, and to evaluate the quality of life of patients with EORTC QLQ-C30. To explore the anti-tumor effect of Shentao Ruangan Prescription combined with sorafenib and its related mechanism, and to provide a certain experiment for targeting Chinese medicine combined with sorafenib in the treatment of primary liver cancer. Methods: 1. Clinical study: Prospective randomized controlled trial was used to study 60 cases, including 30 cases of Chinese medicine combined group and 30 cases of control group. Patients in group A were given oral sorafenib 400 mg twice a day. The patients were followed up monthly to evaluate tumor control, to record disease progression time and survival time, and to monitor liver function indexes such as glutamic-alanine aminotransferase (ALT), total bilirubin (Tbet-IL), albumin (ALB). Recognized Quality of Life Scale EORTC QLQ-C30 was used to follow up the patients'quality of life and evaluate their quality of life. The adverse reactions during the study were recorded by NCI adverse event evaluation criteria to evaluate the drug safety. 2. Experimental study: HepG2 liver cancer xenograft model was constructed in nude mice. Randomly divided into control group, Shentao Ruangan Fang group, Sorafenib group and Shentao Ruangan Fang combined with Sorafenib group, and then given intragastric administration. Tumor volume and weight of mice were measured every three days during the administration period. Tumor weight was measured after administration, and tumor inhibition rate was calculated. The level of vascular endothelial growth factor (VEGF) and the expression of platelet-derived growth factor (PDGF) were measured to explore the mechanism of anti-tumor effect of Shentao Ruangan Prescription combined with sorafenib. VS 10.0%, P 0.05), and the tumor disease control rate (DCR) in the combined group was higher than that in the control group (66.6% VS 46.6%, P 0.05), suggesting that sorafenib combined with Shentao Ruangan Fang can not improve the objective remission rate of liver cancer patients, but can improve the disease control rate. The 3-month survival rate and 6-month survival rate of patients in Ruangan Fang group were no significant difference from those in Sorafenib alone group (51.0% VS 46.6%, 43.7% VS 34.3%, all P 0.05). Compared with the 1-year survival rate of the two groups, the 1-year survival rate of the Chinese medicine combined group was better than that of the control group (38.3% VS 21.7%, P 0.05), suggesting that Sorafenib combined with Shentao Ruangan Fang could not be extracted. The Kaplan-Meier method was used to analyze the disease progression time and survival time of the two groups. The results showed that the median disease progression time (mTTP) of the sorafenib combined with Shentao Ruangan Recipe group was no different from that of the sorafenib alone group. 4.3 months VS 3.6 months, Z = 0.858, P = 0.354), suggesting that the combination of Sorafenib and Shentao Ruangan Recipe group than Sorafenib alone group, the two groups in prolonging the progression of disease in patients with advanced primary liver cancer in no significant difference. The median survival time was 6.1 months, and the combined group was 1.6 months longer than the control group. The difference was statistically significant (Z = 5.998, P = 0.014). Compared with the control group, AFP levels in the combined group and the control group were significantly decreased after treatment, the difference was statistically significant (P 0.01). The difference of AFP levels between the two groups before and after treatment (AFP difference before and after treatment = AFP before and after treatment) showed that the level of AFP in the combined group decreased more significantly than that in the control group (35. 9.83ng/ml VS 266.23ng/ml, P 0.05). It was suggested that after treatment, the serum AFP levels in both groups were significantly decreased, and the level of AFP in the combined group was significantly higher than that in the control group. The serum ALB levels in both groups were significantly higher than those before treatment (P 0.05). The difference was statistically significant (P 0.05). It was suggested that the liver function in both groups was improved to some extent after treatment. Compared with the control group, the difference of ALT and ALB in the combined group was higher than that in the control group, the difference was statistically significant (P 0.05), but there was no significant difference between the two groups before and after TBI treatment (P 0.05), suggesting that the improvement of ALT and ALB in the combined group was better than that in the control group, but there was no difference in the improvement of TBIL between the two groups. The stabilization and improvement rates of liver function grading were 76.7% and 56.7% respectively in the latter two groups. The stabilization and improvement rates of liver function grading in the combined group were significantly higher than those in the control group (P 0.05), suggesting that the improvement of liver function in the combined group was better than that in the control group. Sorafenib combined with Shentao Ruangan Recipe group, patients in the functional areas of the score and the overall health score increased, the difference was statistically significant (all P 0.05); in the symptomatic areas of fatigue, nausea and vomiting, shortness of breath, insomnia, loss of appetite, pain, constipation and diarrhea scores were significantly lower than before treatment (all P 0.05). According to the Chinese version of EORTC QLQ-C30 (V3.0), the higher the scores in functional areas and general health, the better the functional status and quality of life; the higher the score in symptom areas, the more symptoms or problems (the worse the quality of life), suggesting treatment. After treatment, the quality of life in the combined medication group deteriorated in the areas of economic difficulties, and improved in the other areas. In the control group, the scores of functional areas and the overall health status were also increased, the difference was statistically significant (all P 0.05); in the symptomatic areas of shortness of breath, nausea and nausea. The scores of vomiting, insomnia, pain and constipation decreased significantly (all P 0.05), while those of fatigue, loss of appetite, diarrhea and economic difficulties increased (all P 0.05) (see Table 12). The difference of QOL score between the two groups before and after treatment (QOL score difference = QOL score after treatment - QOL score before treatment) showed that the combined group scored better in terms of physical and emotional function in functional areas. The scores of fatigue, nausea and vomiting, shortness of breath, loss of appetite and diarrhea in the combined group were superior to those in the control group (all P 0.05), and the scores of constipation, insomnia, pain and economic difficulties were not significantly different between the two groups (all P 0.05). There was no significant difference between the two groups (all P 0.05), and the scores of the combined group were higher than those of the control group (all P 0.05). In the course of the study, the adverse reactions of the two groups were as follows. Comparing the adverse reactions of the two groups, the results showed that the incidence of hand-foot syndrome, diarrhea, fatigue, skin rash in the combined group was significantly lower than that in the control group (all P 0.05), while the incidence of bone marrow depression in the two groups was significantly lower. There was no significant difference in the incidence of adverse reactions to hypertension (all P 0.05). It was suggested that the combination of sorafenib and Shentao Ruangan Prescription could significantly reduce the incidence of hand-foot syndrome, diarrhea, fatigue, rash and other adverse reactions of sorafenib, but had no significant effect on the incidence of marrow suppression and adverse reactions to hypertension. The results showed that the tumor volume of traditional Chinese medicine group, sorafenib group and combined group was smaller than that of control group (all P 0.05). The tumor volume of sorafenib group was smaller than that of traditional Chinese medicine group (P 0.05). The tumor volume of combined group was smaller than that of sorafenib group (P 0.05), suggesting that Shentao Ruangan Fang had certain inhibitory effect on tumor growth, but its inhibitory effect on tumor was not obvious. The results showed that the tumor weight of traditional Chinese medicine group, sorafenib group and combined group were less than that of control group (P 0.05). The tumor inhibition rate of sorafenib group was better than that of Shentao Ruangan Fang group (44.5% VS 31.9%, P 0.05), while that of combined group was better than that of Shentao Ruangan Fang group (44.5% VS 31.9%, P 0.05). The inhibition rate of Shentao Ruangan Recipe and Sorafenib on hepatoma was higher than that of Shentao Ruangan Recipe (68.7% VS 44.5%, P 0.05), suggesting that both Shentao Ruangan Recipe and Sorafenib had certain inhibitory effect on hepatoma in vivo. The inhibitory effect of Sorafenib on hepatoma was higher than that of Shentao Ruangan Recipe, and the combination of them could further enhance the inhibitory effect on hepatoma. The expression and phosphorylation of PI3K and AKT protein in normal hepatoma HepG2 cells were significantly decreased (all P 0.05). The expression and phosphorylation of PI3K and AKT protein in Sorafenib group, Sorafenib group and Shentao Ruangan Fang group were significantly decreased (all P 0.05). VS. Chinese medicine group and sorafenib group, both P 0.05, while sorafenib group and Chinese medicine group PI3K and AKT protein expression and phosphorylation levels were not significantly different (all P 0.05), suggesting that sorafenib and Shentao Ruangan Formula can inhibit PI3K, AKT protein activity, both of them have the same inhibitory effect on PI3K, AKT, but sorafenib combined with Shentao Ruangan Formula should be used. Western blot also showed that the expression of VEGF and P DGF protein in normal group was high, while the expression of VEGF and P DGF protein in traditional Chinese medicine group, sorafenib group and combined group was significantly lower than that in normal group (all P 0.05). The expression of VEGF and P DGF protein in sorafenib group was lower than that in traditional Chinese medicine group (all P Sorafenib combined with Shentao Ruangan Recipe showed the most significant decrease in the expression of VEGF and PDGF protein (VS. Chinese medicine group and Sorafenib group, both P 0.05), suggesting that both Sorafenib and Shentao Ruangan Recipe could inhibit the expression of VEGF and PDGF protein, and the inhibitory effect of Sorafenib on VEGF and PDGF was better than that of Shentao Ruangan Recipe. Conclusion: 1. Shentao Ruangan Prescription combined with sorafenib can improve the disease control rate and prolong the survival time of patients with advanced primary liver cancer. 2. Shentao Ruangan Prescription combined with sorafenib can improve the quality of life of patients with advanced primary liver cancer. 3. Shentao Ruangan Decoction combined with sorafenib in the treatment of middle and advanced primary stage
【学位授予单位】：广州中医药大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R735.7
[Abstract]:Objective: To observe the curative effect of Shentao Ruangan Prescription combined with sorafenib on advanced primary hepatocellular carcinoma by prospective randomized controlled clinical research method, and to evaluate the quality of life of patients with EORTC QLQ-C30. To explore the anti-tumor effect of Shentao Ruangan Prescription combined with sorafenib and its related mechanism, and to provide a certain experiment for targeting Chinese medicine combined with sorafenib in the treatment of primary liver cancer. Methods: 1. Clinical study: Prospective randomized controlled trial was used to study 60 cases, including 30 cases of Chinese medicine combined group and 30 cases of control group. Patients in group A were given oral sorafenib 400 mg twice a day. The patients were followed up monthly to evaluate tumor control, to record disease progression time and survival time, and to monitor liver function indexes such as glutamic-alanine aminotransferase (ALT), total bilirubin (Tbet-IL), albumin (ALB). Recognized Quality of Life Scale EORTC QLQ-C30 was used to follow up the patients'quality of life and evaluate their quality of life. The adverse reactions during the study were recorded by NCI adverse event evaluation criteria to evaluate the drug safety. 2. Experimental study: HepG2 liver cancer xenograft model was constructed in nude mice. Randomly divided into control group, Shentao Ruangan Fang group, Sorafenib group and Shentao Ruangan Fang combined with Sorafenib group, and then given intragastric administration. Tumor volume and weight of mice were measured every three days during the administration period. Tumor weight was measured after administration, and tumor inhibition rate was calculated. The level of vascular endothelial growth factor (VEGF) and the expression of platelet-derived growth factor (PDGF) were measured to explore the mechanism of anti-tumor effect of Shentao Ruangan Prescription combined with sorafenib. VS 10.0%, P 0.05), and the tumor disease control rate (DCR) in the combined group was higher than that in the control group (66.6% VS 46.6%, P 0.05), suggesting that sorafenib combined with Shentao Ruangan Fang can not improve the objective remission rate of liver cancer patients, but can improve the disease control rate. The 3-month survival rate and 6-month survival rate of patients in Ruangan Fang group were no significant difference from those in Sorafenib alone group (51.0% VS 46.6%, 43.7% VS 34.3%, all P 0.05). Compared with the 1-year survival rate of the two groups, the 1-year survival rate of the Chinese medicine combined group was better than that of the control group (38.3% VS 21.7%, P 0.05), suggesting that Sorafenib combined with Shentao Ruangan Fang could not be extracted. The Kaplan-Meier method was used to analyze the disease progression time and survival time of the two groups. The results showed that the median disease progression time (mTTP) of the sorafenib combined with Shentao Ruangan Recipe group was no different from that of the sorafenib alone group. 4.3 months VS 3.6 months, Z = 0.858, P = 0.354), suggesting that the combination of Sorafenib and Shentao Ruangan Recipe group than Sorafenib alone group, the two groups in prolonging the progression of disease in patients with advanced primary liver cancer in no significant difference. The median survival time was 6.1 months, and the combined group was 1.6 months longer than the control group. The difference was statistically significant (Z = 5.998, P = 0.014). Compared with the control group, AFP levels in the combined group and the control group were significantly decreased after treatment, the difference was statistically significant (P 0.01). The difference of AFP levels between the two groups before and after treatment (AFP difference before and after treatment = AFP before and after treatment) showed that the level of AFP in the combined group decreased more significantly than that in the control group (35. 9.83ng/ml VS 266.23ng/ml, P 0.05). It was suggested that after treatment, the serum AFP levels in both groups were significantly decreased, and the level of AFP in the combined group was significantly higher than that in the control group. The serum ALB levels in both groups were significantly higher than those before treatment (P 0.05). The difference was statistically significant (P 0.05). It was suggested that the liver function in both groups was improved to some extent after treatment. Compared with the control group, the difference of ALT and ALB in the combined group was higher than that in the control group, the difference was statistically significant (P 0.05), but there was no significant difference between the two groups before and after TBI treatment (P 0.05), suggesting that the improvement of ALT and ALB in the combined group was better than that in the control group, but there was no difference in the improvement of TBIL between the two groups. The stabilization and improvement rates of liver function grading were 76.7% and 56.7% respectively in the latter two groups. The stabilization and improvement rates of liver function grading in the combined group were significantly higher than those in the control group (P 0.05), suggesting that the improvement of liver function in the combined group was better than that in the control group. Sorafenib combined with Shentao Ruangan Recipe group, patients in the functional areas of the score and the overall health score increased, the difference was statistically significant (all P 0.05); in the symptomatic areas of fatigue, nausea and vomiting, shortness of breath, insomnia, loss of appetite, pain, constipation and diarrhea scores were significantly lower than before treatment (all P 0.05). According to the Chinese version of EORTC QLQ-C30 (V3.0), the higher the scores in functional areas and general health, the better the functional status and quality of life; the higher the score in symptom areas, the more symptoms or problems (the worse the quality of life), suggesting treatment. After treatment, the quality of life in the combined medication group deteriorated in the areas of economic difficulties, and improved in the other areas. In the control group, the scores of functional areas and the overall health status were also increased, the difference was statistically significant (all P 0.05); in the symptomatic areas of shortness of breath, nausea and nausea. The scores of vomiting, insomnia, pain and constipation decreased significantly (all P 0.05), while those of fatigue, loss of appetite, diarrhea and economic difficulties increased (all P 0.05) (see Table 12). The difference of QOL score between the two groups before and after treatment (QOL score difference = QOL score after treatment - QOL score before treatment) showed that the combined group scored better in terms of physical and emotional function in functional areas. The scores of fatigue, nausea and vomiting, shortness of breath, loss of appetite and diarrhea in the combined group were superior to those in the control group (all P 0.05), and the scores of constipation, insomnia, pain and economic difficulties were not significantly different between the two groups (all P 0.05). There was no significant difference between the two groups (all P 0.05), and the scores of the combined group were higher than those of the control group (all P 0.05). In the course of the study, the adverse reactions of the two groups were as follows. Comparing the adverse reactions of the two groups, the results showed that the incidence of hand-foot syndrome, diarrhea, fatigue, skin rash in the combined group was significantly lower than that in the control group (all P 0.05), while the incidence of bone marrow depression in the two groups was significantly lower. There was no significant difference in the incidence of adverse reactions to hypertension (all P 0.05). It was suggested that the combination of sorafenib and Shentao Ruangan Prescription could significantly reduce the incidence of hand-foot syndrome, diarrhea, fatigue, rash and other adverse reactions of sorafenib, but had no significant effect on the incidence of marrow suppression and adverse reactions to hypertension. The results showed that the tumor volume of traditional Chinese medicine group, sorafenib group and combined group was smaller than that of control group (all P 0.05). The tumor volume of sorafenib group was smaller than that of traditional Chinese medicine group (P 0.05). The tumor volume of combined group was smaller than that of sorafenib group (P 0.05), suggesting that Shentao Ruangan Fang had certain inhibitory effect on tumor growth, but its inhibitory effect on tumor was not obvious. The results showed that the tumor weight of traditional Chinese medicine group, sorafenib group and combined group were less than that of control group (P 0.05). The tumor inhibition rate of sorafenib group was better than that of Shentao Ruangan Fang group (44.5% VS 31.9%, P 0.05), while that of combined group was better than that of Shentao Ruangan Fang group (44.5% VS 31.9%, P 0.05). The inhibition rate of Shentao Ruangan Recipe and Sorafenib on hepatoma was higher than that of Shentao Ruangan Recipe (68.7% VS 44.5%, P 0.05), suggesting that both Shentao Ruangan Recipe and Sorafenib had certain inhibitory effect on hepatoma in vivo. The inhibitory effect of Sorafenib on hepatoma was higher than that of Shentao Ruangan Recipe, and the combination of them could further enhance the inhibitory effect on hepatoma. The expression and phosphorylation of PI3K and AKT protein in normal hepatoma HepG2 cells were significantly decreased (all P 0.05). The expression and phosphorylation of PI3K and AKT protein in Sorafenib group, Sorafenib group and Shentao Ruangan Fang group were significantly decreased (all P 0.05). VS. Chinese medicine group and sorafenib group, both P 0.05, while sorafenib group and Chinese medicine group PI3K and AKT protein expression and phosphorylation levels were not significantly different (all P 0.05), suggesting that sorafenib and Shentao Ruangan Formula can inhibit PI3K, AKT protein activity, both of them have the same inhibitory effect on PI3K, AKT, but sorafenib combined with Shentao Ruangan Formula should be used. Western blot also showed that the expression of VEGF and P DGF protein in normal group was high, while the expression of VEGF and P DGF protein in traditional Chinese medicine group, sorafenib group and combined group was significantly lower than that in normal group (all P 0.05). The expression of VEGF and P DGF protein in sorafenib group was lower than that in traditional Chinese medicine group (all P Sorafenib combined with Shentao Ruangan Recipe showed the most significant decrease in the expression of VEGF and PDGF protein (VS. Chinese medicine group and Sorafenib group, both P 0.05), suggesting that both Sorafenib and Shentao Ruangan Recipe could inhibit the expression of VEGF and PDGF protein, and the inhibitory effect of Sorafenib on VEGF and PDGF was better than that of Shentao Ruangan Recipe. Conclusion: 1. Shentao Ruangan Prescription combined with sorafenib can improve the disease control rate and prolong the survival time of patients with advanced primary liver cancer. 2. Shentao Ruangan Prescription combined with sorafenib can improve the quality of life of patients with advanced primary liver cancer. 3. Shentao Ruangan Decoction combined with sorafenib in the treatment of middle and advanced primary stage
【学位授予单位】：广州中医药大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R735.7
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