本文選題：結(jié)直腸癌 + 晚期��； 參考：《中國中醫(yī)科學院》2017年碩士論文

【摘要】：近年來,隨著醫(yī)學技術(shù)的進步與發(fā)展,惡性腫瘤的治療手段逐漸多樣化,腫瘤患者的生活質(zhì)量、生存期等在不同程度上有了顯著的提高。中醫(yī)藥治療作為我國治療惡性腫瘤的特色方法之一,為腫瘤患者提供了一種簡、便、廉、驗的治療體驗。不少臨床研究已經(jīng)證實,對于西醫(yī)治療效果欠佳或失去治療機會的晚期結(jié)直腸癌患者,采用純中醫(yī)治療或中西醫(yī)結(jié)合治療,能夠在一定程度上延長患者的生存期,提高生活質(zhì)量,改善生活狀態(tài),最終實現(xiàn)長期帶瘤生存。然而在臨床中,我們發(fā)現(xiàn)并非所有的晚期結(jié)直腸癌患者都能從中醫(yī)藥治療取得良好效果,如何尋找到一種更加有效的方法治療晚期結(jié)直腸癌,探索中醫(yī)藥治療后效果較好的人群特征,需要我們不斷地努力。本研究依托于北京市科學技術(shù)委員會“首都特色臨床應(yīng)用項目”,旨在驗證祛邪膠囊治療晚期結(jié)直腸癌的臨床療效,探索中醫(yī)藥干預(yù)治療后的晚期結(jié)直腸癌優(yōu)勢病例與劣勢病例的特點,從而總結(jié)中醫(yī)藥治療的優(yōu)勢人群(受益人群)與劣勢人群(非受益人群)特征,最終實現(xiàn)中醫(yī)藥治療晚期結(jié)直腸癌的精準化、個體化。祛邪膠囊是由中國中醫(yī)科學院西苑醫(yī)院腫瘤科楊宇飛教授,在原中國中醫(yī)科學院院長施奠邦教授的指導(dǎo)下,與吳煜教授共同研制,從古方化裁而來。本方具有溫通經(jīng)脈陽氣,緩消絡(luò)中之積等功效,是治療消化道惡性腫瘤的中藥制劑。楊宇飛主任認為“脈絡(luò)閉阻是腸癌發(fā)病的根本原因,而局部陽氣不達是結(jié)直腸癌的基本病機”,“通陽法”作為防治結(jié)直腸癌總治則,在治療結(jié)直腸癌的過程中發(fā)揮了重要的優(yōu)勢。祛邪膠囊是由明代李中梓所創(chuàng)制的治療積名方“陰陽攻擊丸”化裁而來,全方以溫通為主,攻補兼施,寒溫并用,所以李中梓特別強調(diào),患者無論陰陽寒熱,皆可應(yīng)用。楊宇飛教授自1997年開始致力于此方的臨床研究與應(yīng)用,至今已有20年的歷史。經(jīng)楊宇飛主任團隊的不懈努力,數(shù)個基礎(chǔ)研究及臨床試驗初步證實:祛邪膠囊在早中期、晚期結(jié)直腸癌治療中均具有一定的作用。本次研究為進一步證實祛邪膠囊的療效,在前期研究的基礎(chǔ)上,擴大了樣本量,并對中醫(yī)藥干預(yù)治療后的優(yōu)劣勢病例特點進行了探討分析,初步描述了優(yōu)勢人群與劣勢人群的臨床特征。本文共分為文獻綜述、隨機雙盲對照研究和描述性研究三部分。首先從病名、病因病機、辨證論治的角度綜述了中醫(yī)理論對結(jié)直腸癌的認識,其次對中醫(yī)藥在晚期結(jié)直腸癌中的研究進展展開綜述。臨床研究部分主要包括:隨機雙盲對照研究及人群特征描述性研究。隨機對照研究主要針對祛邪膠囊治療晚期結(jié)直腸癌的臨床療效進行展開。人群特征描述性研究,首先采用專家咨詢法制定最佳最差病例篩選標準,并根據(jù)此標準篩選中醫(yī)藥干預(yù)治療后的優(yōu)勢病例與劣勢病例,通過對優(yōu)劣勢病例特點進行描述分析,從而初步總結(jié)優(yōu)勢人群(受益人群)與劣勢人群(非受益人群)的臨床特征。研究一:祛邪膠囊治療晚期結(jié)直腸癌的隨機雙盲對照研究目的:客觀評價祛邪膠囊治療晚期結(jié)直腸癌的臨床療效,并對祛邪膠囊的安全性進行評價。方法:采用隨機、雙盲、對照的臨床研究方法,將符合納入標準的72例晚期結(jié)直腸癌患者按1:1的比例隨機分為治療組(36例)和對照組(36例)。治療組在常規(guī)治療的基礎(chǔ)上加用祛邪膠囊,對照組在常規(guī)治療的基礎(chǔ)上加用安慰劑膠囊。分別干預(yù)治療3個月后,進行長期隨訪,直至患者死亡。隨訪內(nèi)容主要包括:患者的生存情況(OS/mOS)、腫瘤進展情況(PFS)、生活質(zhì)量評分、中醫(yī)癥狀評分、腫瘤標志物、肝腎功能、血常規(guī)等內(nèi)容。本課題通過了我院倫理委員會倫理審查工作,執(zhí)行期間由北京市岐黃藥品臨床研究中心(第三方公司)負責監(jiān)察工作,并進行了國內(nèi)臨床試驗注冊,取得了臨床試驗注冊統(tǒng)一編號,編號為ChiCTR-IOR-16008924。結(jié)果:1、治療組、對照組在性別方面存在統(tǒng)計學差異,其中治療組女性患者明顯多于對照組(P0.05)。其他一般資料如年齡、發(fā)病部位、生活質(zhì)量評分等方面均未見明顯統(tǒng)計學差異(P0.05)。2、治療組的Ⅳ期中位生存時間為41個月,對照組的Ⅳ期中位生存時間為30個月,治療組較對照組延長了 11個月(P=0.030.05)。而兩組患者入組前Ⅳ期生存時間未見明顯差異(P=0.140.05),治療組患者入組前平均Ⅳ期生存時間為16.00±11.80個月,對照組患者入組前平均Ⅳ期生存時間為11.4±9.5個月。3、治療組的入組后中位生存期(mOS)為18個月,對照組的入組后中位生存期為16個月,治療組與對照組未見統(tǒng)計學差異(P=0.200.05)4、治療組的中位無進展生存期(mPFS)為6.17個月,對照組的中位無進展生存期為5.87個月,治療組與對照組相比未見統(tǒng)計學差異(P=0.950.05)。5、祛邪膠囊干預(yù)治療前后,在生活質(zhì)量如軀體功能、角色功能、認知、情感、社會功能等方面均有改善,且治療組優(yōu)于對照組,具有統(tǒng)計學差異(P=0.0180.05)。6、治療后第15個月,治療組的部分緩解(PR)率為0%,疾病穩(wěn)定(SD)率為77.78%;對照組的部分緩解率為14.29%,疾病穩(wěn)定率為42.86%。治療組的腫瘤控制率(RR=CR+PR+SD)(77.78%)與對照組的腫瘤控制率(57.15%)相比未見統(tǒng)計學差異(P=0.710.05)。治療組的中醫(yī)癥候、主癥評分的改變較對照組未見統(tǒng)計學差異(P0.05)。7、本研究實施期間,未發(fā)生嚴重不良事件。72例患者共發(fā)生22例27例次不良事件,其中治療組9例10例次,發(fā)生率為25%;對照組13例17次,發(fā)生率為36.11%。判定為與研究藥物可能相關(guān)的不良事件為胃痛,治療組發(fā)生2例,發(fā)生率為5.56%,對照組發(fā)生1例,發(fā)生率為2.27%。研究二:中醫(yī)藥干預(yù)治療晚期結(jié)直腸癌的優(yōu)劣勢病例特點初步探討目的:篩選中醫(yī)藥干預(yù)治療后的最佳病例與最差病例,通過對優(yōu)劣勢病例特點進行總結(jié),從而描述優(yōu)勢人群(受益人群)與劣勢人群(非受益人群)的臨床特征。方法:結(jié)合國際晚期結(jié)直腸癌生存期最新研究數(shù)據(jù),采用專家咨詢法,共咨詢?nèi)珖[瘤專家32名,從生存期及基因分型的角度對最佳最差病例標準進行了制定。將入組的72例患者作為整體觀察對象,并根據(jù)此篩選標準篩選最佳/最差病例。分別對兩組病例的性別、年齡、發(fā)病部位、基因分型、中醫(yī)證型等內(nèi)容進行描述性分析。結(jié)果:1、采取專家咨詢法,制定了最佳/最差病例的定義,具體標準如下:最差病例:Ⅳ期生存期≤12個月。最佳病例:KRAS、NRAS、BRAF全野生型Ⅳ期生存期30個月,RAS有一項突變型Ⅳ期生存期24個月,B-RAF-突變型Ⅳ期生存期18個月。根據(jù)最佳最差病例定義標準,從72例患者中篩選出最佳病例38例,從已經(jīng)獲得生存結(jié)局的病例中篩選出最差病例7例。2、最佳病例組的特點:性別: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%)。年齡分布:最佳病例組年齡分布主要集中在40-59年齡段(36.8%),其次是60-69 年齡段(34.2%)。發(fā)病部位:左側(cè)結(jié)直腸癌30例(占全部最佳病例的78.9%),右側(cè)結(jié)直腸癌8例(占全部最佳病例的21.1%)�；蚍中�:KRAS、NRAS、BRAF—全野生型的比例為50%;KRAS,NRAS—突變型,BRAF—野生型的比例為42.1%;BRAF—突變型,KRAS,NRAS—野生型的比例為7.9%。中醫(yī)證型:最佳病例組中脾腎虧虛占有較大的比例(均占全部最佳病例的34.2%);肝郁脾虛型占26.3%,肝腎虧虛占23.7%。3、最差病例組的特點:性別: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%)。年齡分布:最差病例組的年齡組要集中在60—70年齡段(57.1%)。發(fā)病部位:7例最差病例全部為左側(cè)結(jié)直腸癌�；蚍中�:KRAS、NRAS、BRAF—全野生型的比例為57.1%,KRAS、NRAS—突變型,BRAF—野生型的比例為42.9%,未見BRAF—突變型患者。中醫(yī)證型方面:最差病例組中肝腎虧虛證型所占的比例較大,約為57.1%,肺腎虧虛型占28.6%,脾腎虧虛型占14.3%。結(jié)論:祛邪膠囊干預(yù)治療能夠延長晚期結(jié)直腸癌患者的Ⅳ期中位生存期,提高患者的生活質(zhì)量,而對于腫瘤無進展生存期并無顯著影響,提示祛邪膠囊對于晚期腸癌的治療療效并非針對瘤體本身,患者從祛邪膠囊治療中可以獲得遠期生存獲益。中醫(yī)藥干預(yù)治療晚期結(jié)直腸癌的臨床療效,可能與患者的年齡、中醫(yī)證型等內(nèi)容有關(guān)。其中40-59歲年齡段的晚期結(jié)直腸癌患者可能會從中醫(yī)治療中獲益,而60-69歲年齡段的患者可能從中醫(yī)藥治療中獲益較少。另外,中醫(yī)辨證為脾腎虧虛型的患者可能會從中醫(yī)藥干預(yù)治療中獲益,而辨證為肝腎虧虛型的患者可能從中醫(yī)藥干預(yù)治療中的獲益較少。
[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.
【學位授予單位】：中國中醫(yī)科學院
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R273

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