祛邪胶囊治疗晚期结直肠癌的随机对照研究及优劣势病例特点初探

发布时间：2018-06-07 09:25

本文选题：结直肠癌 + 晚期　；参考：《中国中医科学院》2017年硕士论文

【摘要】：近年来,随着医学技术的进步与发展,恶性肿瘤的治疗手段逐渐多样化,肿瘤患者的生活质量、生存期等在不同程度上有了显著的提高。中医药治疗作为我国治疗恶性肿瘤的特色方法之一,为肿瘤患者提供了一种简、便、廉、验的治疗体验。不少临床研究已经证实,对于西医治疗效果欠佳或失去治疗机会的晚期结直肠癌患者,采用纯中医治疗或中西医结合治疗,能够在一定程度上延长患者的生存期,提高生活质量,改善生活状态,最终实现长期带瘤生存。然而在临床中,我们发现并非所有的晚期结直肠癌患者都能从中医药治疗取得良好效果,如何寻找到一种更加有效的方法治疗晚期结直肠癌,探索中医药治疗后效果较好的人群特征,需要我们不断地努力。本研究依托于北京市科学技术委员会“首都特色临床应用项目”,旨在验证祛邪胶囊治疗晚期结直肠癌的临床疗效,探索中医药干预治疗后的晚期结直肠癌优势病例与劣势病例的特点,从而总结中医药治疗的优势人群(受益人群)与劣势人群(非受益人群)特征,最终实现中医药治疗晚期结直肠癌的精准化、个体化。祛邪胶囊是由中国中医科学院西苑医院肿瘤科杨宇飞教授,在原中国中医科学院院长施奠邦教授的指导下,与吴煜教授共同研制,从古方化裁而来。本方具有温通经脉阳气,缓消络中之积等功效,是治疗消化道恶性肿瘤的中药制剂。杨宇飞主任认为“脉络闭阻是肠癌发病的根本原因,而局部阳气不达是结直肠癌的基本病机”,“通阳法”作为防治结直肠癌总治则,在治疗结直肠癌的过程中发挥了重要的优势。祛邪胶囊是由明代李中梓所创制的治疗积名方“阴阳攻击丸”化裁而来,全方以温通为主,攻补兼施,寒温并用,所以李中梓特别强调,患者无论阴阳寒热,皆可应用。杨宇飞教授自1997年开始致力于此方的临床研究与应用,至今已有20年的历史。经杨宇飞主任团队的不懈努力,数个基础研究及临床试验初步证实:祛邪胶囊在早中期、晚期结直肠癌治疗中均具有一定的作用。本次研究为进一步证实祛邪胶囊的疗效,在前期研究的基础上,扩大了样本量,并对中医药干预治疗后的优劣势病例特点进行了探讨分析,初步描述了优势人群与劣势人群的临床特征。本文共分为文献综述、随机双盲对照研究和描述性研究三部分。首先从病名、病因病机、辨证论治的角度综述了中医理论对结直肠癌的认识,其次对中医药在晚期结直肠癌中的研究进展展开综述。临床研究部分主要包括:随机双盲对照研究及人群特征描述性研究。随机对照研究主要针对祛邪胶囊治疗晚期结直肠癌的临床疗效进行展开。人群特征描述性研究,首先采用专家咨询法制定最佳最差病例筛选标准,并根据此标准筛选中医药干预治疗后的优势病例与劣势病例,通过对优劣势病例特点进行描述分析,从而初步总结优势人群(受益人群)与劣势人群(非受益人群)的临床特征。研究一:祛邪胶囊治疗晚期结直肠癌的随机双盲对照研究目的:客观评价祛邪胶囊治疗晚期结直肠癌的临床疗效,并对祛邪胶囊的安全性进行评价。方法:采用随机、双盲、对照的临床研究方法,将符合纳入标准的72例晚期结直肠癌患者按1:1的比例随机分为治疗组(36例)和对照组(36例)。治疗组在常规治疗的基础上加用祛邪胶囊,对照组在常规治疗的基础上加用安慰剂胶囊。分别干预治疗3个月后,进行长期随访,直至患者死亡。随访内容主要包括:患者的生存情况(OS/mOS)、肿瘤进展情况(PFS)、生活质量评分、中医症状评分、肿瘤标志物、肝肾功能、血常规等内容。本课题通过了我院伦理委员会伦理审查工作,执行期间由北京市岐黄药品临床研究中心(第三方公司)负责监察工作,并进行了国内临床试验注册,取得了临床试验注册统一编号,编号为ChiCTR-IOR-16008924。结果:1、治疗组、对照组在性别方面存在统计学差异,其中治疗组女性患者明显多于对照组(P0.05)。其他一般资料如年龄、发病部位、生活质量评分等方面均未见明显统计学差异(P0.05)。2、治疗组的Ⅳ期中位生存时间为41个月,对照组的Ⅳ期中位生存时间为30个月,治疗组较对照组延长了 11个月(P=0.030.05)。而两组患者入组前Ⅳ期生存时间未见明显差异(P=0.140.05),治疗组患者入组前平均Ⅳ期生存时间为16.00±11.80个月,对照组患者入组前平均Ⅳ期生存时间为11.4±9.5个月。3、治疗组的入组后中位生存期(mOS)为18个月,对照组的入组后中位生存期为16个月,治疗组与对照组未见统计学差异(P=0.200.05)4、治疗组的中位无进展生存期(mPFS)为6.17个月,对照组的中位无进展生存期为5.87个月,治疗组与对照组相比未见统计学差异(P=0.950.05)。5、祛邪胶囊干预治疗前后,在生活质量如躯体功能、角色功能、认知、情感、社会功能等方面均有改善,且治疗组优于对照组,具有统计学差异(P=0.0180.05)。6、治疗后第15个月,治疗组的部分缓解(PR)率为0%,疾病稳定(SD)率为77.78%;对照组的部分缓解率为14.29%,疾病稳定率为42.86%。治疗组的肿瘤控制率(RR=CR+PR+SD)(77.78%)与对照组的肿瘤控制率(57.15%)相比未见统计学差异(P=0.710.05)。治疗组的中医症候、主症评分的改变较对照组未见统计学差异(P0.05)。7、本研究实施期间,未发生严重不良事件。72例患者共发生22例27例次不良事件,其中治疗组9例10例次,发生率为25%;对照组13例17次,发生率为36.11%。判定为与研究药物可能相关的不良事件为胃痛,治疗组发生2例,发生率为5.56%,对照组发生1例,发生率为2.27%。研究二:中医药干预治疗晚期结直肠癌的优劣势病例特点初步探讨目的:筛选中医药干预治疗后的最佳病例与最差病例,通过对优劣势病例特点进行总结,从而描述优势人群(受益人群)与劣势人群(非受益人群)的临床特征。方法:结合国际晚期结直肠癌生存期最新研究数据,采用专家咨询法,共咨询全国肿瘤专家32名,从生存期及基因分型的角度对最佳最差病例标准进行了制定。将入组的72例患者作为整体观察对象,并根据此筛选标准筛选最佳/最差病例。分别对两组病例的性别、年龄、发病部位、基因分型、中医证型等内容进行描述性分析。结果:1、采取专家咨询法,制定了最佳/最差病例的定义,具体标准如下:最差病例:Ⅳ期生存期≤12个月。最佳病例:KRAS、NRAS、BRAF全野生型Ⅳ期生存期30个月,RAS有一项突变型Ⅳ期生存期24个月,B-RAF-突变型Ⅳ期生存期18个月。根据最佳最差病例定义标准,从72例患者中筛选出最佳病例38例,从已经获得生存结局的病例中筛选出最差病例7例。2、最佳病例组的特点:性别:男性22例(占全部最佳病例的57.9%),女性16例(占全部最佳病例的 42.1%)。年龄分布:最佳病例组年龄分布主要集中在40-59年龄段(36.8%),其次是60-69 年龄段(34.2%)。发病部位:左侧结直肠癌30例(占全部最佳病例的78.9%),右侧结直肠癌8例(占全部最佳病例的21.1%)。基因分型:KRAS、NRAS、BRAF—全野生型的比例为50%;KRAS,NRAS—突变型,BRAF—野生型的比例为42.1%;BRAF—突变型,KRAS,NRAS—野生型的比例为7.9%。中医证型:最佳病例组中脾肾亏虚占有较大的比例(均占全部最佳病例的34.2%);肝郁脾虚型占26.3%,肝肾亏虚占23.7%。3、最差病例组的特点:性别:男性5例(占全部最差病例的71.4%),女性2例(占全部最差病例的28.6%)。年龄分布:最差病例组的年龄组要集中在60—70年龄段(57.1%)。发病部位:7例最差病例全部为左侧结直肠癌。基因分型:KRAS、NRAS、BRAF—全野生型的比例为57.1%,KRAS、NRAS—突变型,BRAF—野生型的比例为42.9%,未见BRAF—突变型患者。中医证型方面:最差病例组中肝肾亏虚证型所占的比例较大,约为57.1%,肺肾亏虚型占28.6%,脾肾亏虚型占14.3%。结论:祛邪胶囊干预治疗能够延长晚期结直肠癌患者的Ⅳ期中位生存期,提高患者的生活质量,而对于肿瘤无进展生存期并无显著影响,提示祛邪胶囊对于晚期肠癌的治疗疗效并非针对瘤体本身,患者从祛邪胶囊治疗中可以获得远期生存获益。中医药干预治疗晚期结直肠癌的临床疗效,可能与患者的年龄、中医证型等内容有关。其中40-59岁年龄段的晚期结直肠癌患者可能会从中医治疗中获益,而60-69岁年龄段的患者可能从中医药治疗中获益较少。另外,中医辨证为脾肾亏虚型的患者可能会从中医药干预治疗中获益,而辨证为肝肾亏虚型的患者可能从中医药干预治疗中的获益较少。
[Abstract]:In recent years, with the progress and development of medical technology, the treatment of malignant tumor has been gradually diversified. The quality of life and life of the cancer patients have been greatly improved in different degrees. As one of the characteristic methods of treating malignant tumors in China, the treatment of traditional Chinese medicine has provided a simple, convenient, cheap and effective treatment experience for the patients with swelling. Many clinical studies have confirmed that the treatment of advanced colorectal cancer patients with poor treatment effect or loss of treatment in western medicine can extend the life of the patients to a certain extent, improve the quality of life, improve the living condition, and ultimately live with the tumor. However, in clinical, we are in the clinic. It is found that not all patients with advanced colorectal cancer can get good results from traditional Chinese medicine. How to find a more effective method for the treatment of advanced colorectal cancer and explore the characteristics of the people with better effect after Chinese medicine treatment needs our continuous efforts. This study is based on the "capital characteristics of the Beijing Municipal Science and Technology Commission" The clinical application project "aims to verify the clinical efficacy of expelling pathogenic capsule in the treatment of advanced colorectal cancer, explore the characteristics of superior and inferior cases of advanced colorectal cancer after Chinese medicine intervention, so as to sum up the advantages of traditional Chinese medicine (beneficiary population) and disadvantaged people (non beneficiaries) and finally realize the late treatment of traditional Chinese medicine." The precision and individualization of the period of colorectal cancer is made by Professor Yang Yufei, Professor of the cancer Department of Xiyuan Hospital of the Chinese Academy of traditional Chinese medicine (Chinese Academy of Chinese Medicine). Under the guidance of Professor Shi Dianbang, the former president of the Chinese Academy of Chinese medicine, Professor Wu Yu, together with Professor Wu Yu, comes from the ancient recipe. The Chinese medicine preparation of the malignant tumor of the Tao. Director Yang Yufei thinks that "the choroid closure is the fundamental cause of the colorectal cancer, and the local Yang Qi is the basic pathogenesis of colorectal cancer". The "Tong Yang method", as the general rule for the prevention and treatment of colorectal cancer, has played a important role in the treatment of colorectal cancer. It was created by Li Zhongzi in the Ming Dynasty. The prescription of "Yin and Yang attack pill" is made, and the whole prescription is mainly Wen Tong, and the attack and supplement are applied, cold and warm, so Li Zhongzi especially emphasizes that patients can be applied regardless of the cold and heat of yin and Yang. Professor Yang Yufei has been working on the clinical research and application of this side since 1997. It has been 20 years since the team of director Yang Yufei did not. Several basic studies and clinical trials have preliminarily confirmed that the expelling pathogenic capsule has a certain role in the early and middle stage of the treatment of advanced colorectal cancer. This study is to further confirm the curative effect of the expelling pathogenic capsule. On the basis of the previous study, the sample size is enlarged and the characteristics of the good and bad cases after the intervention and treatment of Chinese medicine have been explored. The clinical features of the dominant and disadvantaged people were briefly described. This article was divided into three parts: literature review, randomized double blind control study and descriptive study. First, the knowledge of colorectal cancer was reviewed from the point of view of disease, etiology, pathogenesis and syndrome differentiation. Secondly, the study of traditional Chinese medicine in advanced colorectal cancer was carried out. The clinical research part mainly includes: the randomized double blind control study and the population characteristic descriptive study. The randomized controlled study is mainly aimed at the clinical efficacy of the expelling pathogenic capsule in the treatment of advanced colorectal cancer. This standard selects the dominant and inferior cases of Chinese medicine after intervention and treatment. Through the description and analysis of the characteristics of the superior and inferior cases, the clinical features of the dominant population (beneficiary population) and the disadvantaged people (non beneficiary) are summarized. To evaluate the clinical efficacy of expelling Qi capsule in the treatment of advanced colorectal cancer and evaluate the safety of qqc. Methods: 72 patients with advanced colorectal cancer were randomly divided into treatment group (36 cases) and control group (36 cases) according to the proportion of 1:1. The treatment group was treated with routine treatment. A placebo capsule was added to the control group on the basis of conventional treatment. After 3 months of intervention, the control group was followed up for a long period of follow-up until the patient died. The follow-up contents include the survival of the patients (OS/mOS), the tumor progression (PFS), the quality of living quality score, the TCM symptom score, the tumor markers, the liver and kidney function, Through the ethical review of the ethics committee of our hospital, the subject was carried out by the Beijing Qi Huang drug clinical research center (third party company) in charge of supervision, and registered the clinical trials in China. The registration number of the clinical trial was numbered as ChiCTR-IOR-16008924.: 1, the treatment group and the control. There were statistically significant differences in gender, among which the treatment group was significantly more than the control group (P0.05). Other general data, such as age, location and quality of life score, were not significantly different (P0.05).2. The median survival time of the treatment group was 41 months, and the median survival time of the control group was 30 months. The treatment group was longer than the control group for 11 months (P=0.030.05). But there was no significant difference between the two groups before the group IV survival time (P=0.140.05). The average IV survival time of the patients in the treatment group was 16 + 11.80 months before the group entered the group, and the average IV survival time of the control group was 11.4 + 9.5 months.3 before the group entered the group. The period (mOS) was 18 months, and the median survival time of the control group was 16 months. The treatment group and the control group had no statistical difference (P=0.200.05) 4, the median progression free survival (mPFS) was 6.17 months in the treatment group, and the median progression free survival time of the control group was 5.87 months. The treatment group was not statistically different from the control group (P=0.950.05).5, dispelling evil spirits. Before and after the capsule intervention, the quality of life, such as body function, role function, cognition, emotion and social function were improved, and the treatment group was better than the control group, with statistical difference (P=0.0180.05).6, Fifteenth months after treatment, the rate of partial remission (PR) in the treatment group was 0%, the rate of disease stability (SD) was 77.78%, and the partial remission rate of the control group was 77.78%. 14.29%, the tumor control rate (RR=CR+PR+SD) in the 42.86%. treatment group (77.78%) was not significantly different from that of the control group (57.15%). The change of TCM syndrome in the treatment group was not statistically different than that of the control group (P0.05).7, and there was no serious adverse event.72 during the period of the study. There were 22 cases of 27 cases of adverse events in the patients, of which 9 cases in the treatment group were 10 times, the incidence was 25%, the control group 13 cases 17 times, the incidence of 36.11%. determined that the adverse events associated with the study drug may be stomach pain, the treatment group occurred 2 cases, the incidence was 5.56%, the control group was 1 cases, the incidence was 2.27%. study two: TCM Intervention late intervention treatment late. Preliminary study on the advantages and disadvantages of pros and cons of colorectal cancer. Objective: to screen the best cases and worst cases after the intervention of traditional Chinese medicine, and to summarize the characteristics of the superior and inferior cases, so as to describe the clinical characteristics of the dominant population (beneficiary population) and the disadvantaged people (non beneficiaries). The new research data, using the expert consultation method, consulted 32 national cancer experts, made the best and worst case standard from the angle of survival and genotyping. 72 patients were selected as the overall observation object, and the best / worst cases were selected according to the screening criteria. The sex, age and location of the two groups were respectively. Descriptive analysis of genotyping and TCM syndrome types. Results: 1, the best / worst case definition was established by expert consultation. The specific criteria are as follows: the worst case: the stage IV survival is less than 12 months. The best case: KRAS, NRAS, BRAF all wild type IV survival period 30 months, RAS has a mutant IV survival period of 24 months, B-RAF- The mutant type IV survival period was 18 months. According to the best worst case definition standard, 38 cases were selected from 72 patients. The worst cases were screened out of 7 cases of the worst cases from the case of the survival outcome. The best case group was characterized by sex: male 22 cases (57.9% of the best cases), and 16 women (42.1% of all the best cases). Age distribution: the age distribution in the best case group was mainly concentrated in the 40-59 age group (36.8%), followed by the 60-69 age group (34.2%). 30 cases of left colorectal cancer (78.9% of all the best cases), and 8 cases of right colorectal cancer (21.1% of the best cases). The proportion of KRAS, NRAS, BRAF - all wild type was 50%; KRAS, NRAS The proportion of mutant type, BRAF - wild type was 42.1%; the proportion of BRAF - mutant, KRAS, NRAS - wild type was 7.9%. syndrome type: the best case group had a large proportion of spleen and kidney deficiency (all 34.2% of all the best cases); the liver depression and spleen deficiency accounted for 26.3%, the liver and kidney deficiency accounted for 23.7%.3, the worst case group was characterized by sex: male 5 cases (all the total). 71.4% of the worst cases (71.4%), 2 women (28.6% of the worst cases). Age distribution: the age group of the worst case group should be concentrated in the 60 to 70 age group (57.1%). The site of the onset: 7 cases of the worst cases were all left colorectal cancer. Genotyping: the proportion of KRAS, NRAS, BRAF - all wild type was 57.1%, KRAS, NRAS mutant, BRAF - wild type The proportion of the patients was 42.9%, and there was no BRAF mutation. In the case of TCM syndrome, the proportion of the deficiency syndrome of liver and kidney in the worst case group was large, about 57.1%, the deficiency of the lung and kidney was 28.6%, the deficiency of the spleen and kidney was 14.3%. conclusion: the intervention therapy of expelling evil spirits can prolong the middle stage of the middle stage of the stage IV of the patients with advanced colorectal cancer and improve the life of the patients. The quality of the tumor has no significant influence on the progression free survival of the tumor. It suggests that the curative effect of the expelling Qi capsule for advanced colon cancer is not aimed at the tumor body itself. The patients can gain the long-term survival benefit from the treatment of the expelling pathogenic capsule. The clinical efficacy of TCM intervention in the treatment of advanced colorectal cancer may be related to the age of the patients and the TCM syndrome type. At the age of 40-59, patients with advanced colorectal cancer may benefit from traditional Chinese medicine, while 60-69 year old patients may benefit less from traditional Chinese medicine. In addition, patients with spleen and kidney deficiency syndrome may benefit from traditional Chinese medicine intervention therapy, and patients with liver kidney deficiency syndrome may be derived from the Chinese Medicine. The benefits of medical intervention are less.
【学位授予单位】：中国中医科学院
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R273

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