生脉散加味联合DC-CIK对恶性肿瘤患者生存质量及免疫指标影响的临床研究

发布时间：2018-07-16 16:26

【摘要】：研究背景：肺癌的发病率据最新统计结果显示,居恶性肿瘤的第二位,非小细胞肺癌(non-small cell lung cancer, NSCLC)约占80%。近年来,NSCLC的诊断和治疗虽然取得了很大进步,但是晚期NSCLC患者仍占很大比例,死亡率一直居高不下。免疫治疗是一种新型的肿瘤治疗手段,目前已经成为继手术、放疗、化疗后的第四大肿瘤治疗方法,是近年来肿瘤研究领域的研究热点之一。目前,国内研究及技术较为成熟的免疫治疗方法包括：细胞因子诱导的杀伤细胞(CIK)、将树突状细胞(DC)与CIK共培养后的DC-CIK细胞免疫治疗、DC瘤苗、淋巴因子激活的杀伤细胞(LAK)以及肿瘤浸润淋巴细胞(TIL)等。其中DC-CIK细胞,经过体外实验证实具有高效的增殖能力和抗肿瘤活性,且其有区别于传统细胞毒性药物的治疗特点,如安全性高,毒副作用小等,因此被广泛应用于恶性肿瘤综合治疗中。在临床应用中,其且显示了明显的治疗优势,能够显著改善患者生存质量,延长患者生存时间等。但随着研究的深入,越来越多的学者认识到：免疫治疗的治疗疗效出现的时间较长,当应用传统的肿瘤评价方法评价为进展后,仍有可能是免疫治疗的反应阶段,在延长观察时间后出现病情缓解。因此,传统肿瘤评价标准并不能准确的评估免疫治疗的疗效,我们迫切需要寻找一种新的评估方法。随着医学模式的转变,生物-心理-社会医学模式已经逐渐被患者及医疗工作者所认同。临床结局的评价关注的不仅仅是肿瘤疾病本身,更应包括患者身体健康状况、心理状况、社会关系以及肿瘤相关症状的改善等,尤其是针对肿瘤晚期,身体虚弱,不能耐受积极抗肿瘤治疗的NSCLC患者,片面追求肿瘤大小的改变显然不明智,而生存质量评价则意义重大。细胞免疫治疗具有安全性高、毒副作用小的特点,可以应用于晚期肿瘤患者,提高患者生存质量。因此,本研究针对晚期NSCLC患者开展生脉散加减联合DC-CIK细胞免疫治疗,以生存质量为评价指标。晚期NSCLC患者,尤其是经历过放疗、化疗后的患者,极易出现气阴两虚证型。经过长期中医临床实践证实,生脉散具有良好的益气养阴生津作用,加减祛瘀解毒类中药,对NSCLC晚期气阴两虚证患者症状的改善有明显作用,对部分患者气阴两虚病理本质也有明显改善,最终提高患者生存质量。目的：1.本课题旨在研究生脉散加减联合DC-CIK细胞免疫治疗对晚期NSCLC患者生存质量及中医证候的影响,分析基于中医理论建立的生存质量量表与中医证候积分相关性,为建立科学、有效的中西医结合治疗NSCLC及临床评价方法提供循证医学证据。2.通过实验研究探讨了辅助性T细胞17(Th17细胞)在生脉散加减联合DC-CIK细胞免疫治疗恶性肿瘤前后的变化及意义,为细胞免疫治疗患者免疫功能状态评价提供新思路。方法：1.临床试验部分纳入符合纳入标准的NSCLC气阴两虚证患者60例,分为阳性对照组15例,单纯给予DC-CIK细胞免疫治疗；中药对照组30例,给予生脉散加减的中药汤剂口服治疗；联合治疗组15例,给予以上两种方法联合治疗。评价治疗前后3组患者KPS评分：生存质量评分,包括欧洲癌症研究与治疗组织(EORTC)的生活质量核心30问卷调查(QLQ-C30),以及基于中医理论的恶性肿瘤生活质量评价体系之共性量表(QLASTCM-GM);中医证候积分以及免疫功能状态。比较分析QLASTCM-GM和QLQ-C30与中医证候积分的相关性2.实验研究部分纳入中医辨证为气阴两虚型恶性肿瘤患者30例,治疗组15例采用生脉散口服联合DC-CIK免疫治疗,对照组15例用DC-CIK细胞免疫治疗(脱落2例),另外纳入健康人8例作为对照组。采用流式细胞仪检测患者及健康人外周血中Th17细胞。结果：1.应用QLQ-C30评价晚期NSCLC患者生存质量,中药治疗和细胞免疫治疗均能提高患者躯体功能评分,改善患者疲乏症状,从而提高患者生存质量。中药治疗改善患者排便困难优于细胞免疫治疗。细胞免疫治疗提高患者睡眠质量方面优于中药治疗。2.应用QLASTCM-GM评价生存质量,组间比较在形神一体领域,联合治疗组较中药对照组生存质量更高(P＝0.020)；组内比较,治疗后较治疗前生存质量均有所提高。在天人相应领域组间比较无统计学差异,但中药对照组与联合治疗组治疗前后比较均有统计学差异(P0.05)。因此推断：联合中药治疗后,可以更好的提高患者生存质量。3.中医证候积分比较,联合治疗组的临床获益优于中药对照组,P0.05,有统计学差异。4.中医证候积分与QLASTCM-GM量表形神一体领域有中度相关的趋势；与QLQ-C30量表仅在疲乏、呼吸困难以及失眠领域有相关趋势。QLASTCM-GM量表中形神一体领域与QLQ-C30量表躯体功能领域有中度相关趋势。5.气阴两虚型恶性肿瘤患者外周血Thl7表达水平高于健康成年人。细胞免疫治疗后,患者外周血表达Th17水平下降。治疗组较对照组Th17表达水平有下降更多的趋势。结论：1DC-CIK细胞免疫治疗可以提高气阴两虚型晚期NSCLC患者生存质量,与生脉散联合应用具有协同效应。2.生存质量的评价：与QLQ-C30量表相比,QLASTCM-GM量表与中医证候积分更相关,值得进一步研究。3.Th17细胞是恶性肿瘤患者免疫紊乱的产物,生脉散联合细胞免疫治疗后其表达水平明显下降,表明其对患者免疫功能状态的判定有一定的价值,有可能成为免疫治疗后评价机体免疫功能状态的新指标。
[Abstract]:Background: the incidence of lung cancer, according to the latest statistical results, shows that the second cases of malignant tumors, non small cell lung cancer (non-small cell lung cancer, NSCLC) account for about 80%. in recent years. Although great progress has been made in the diagnosis and treatment of NSCLC, the rate of late NSCLC patients still occupies a large proportion and the mortality rate has remained high. Immunotherapy is the same. A new method of tumor therapy has become one of the fourth major tumor treatment methods following surgery, radiotherapy and chemotherapy. It is one of the hotspots in the field of cancer research in recent years. At present, the more mature methods of immunotherapy in China include cytokine induced killer cells (CIK), dendritic cells (DC) and CIK Co cultured DC-CIK cell immunotherapy, DC tumor vaccine, lymphokine activated killer cells (LAK) and tumor infiltrating lymphocyte (TIL), among which DC-CIK cells proved to have high proliferative and antitumor activity in vitro, and they are different from traditional cytotoxic drugs, such as high safety and toxic side effects. It is widely used in the comprehensive treatment of malignant tumor. In clinical application, it shows obvious therapeutic advantage. It can significantly improve the quality of life and prolong the survival time of the patients. However, more and more scholars have realized that the treatment effect of immunotherapy has a long time and is used as an application. The traditional evaluation method of tumor evaluation is still likely to be the reaction stage of immunotherapy, and it is remission after prolonging the observation time. Therefore, the traditional tumor evaluation standard does not accurately evaluate the effect of immunotherapy. We urgently need to find a new evaluation method. With the change of the medical model, the biological psychology is changed. - the social medical model has gradually been recognized by patients and medical workers. The evaluation of clinical outcomes is concerned not only with the tumor itself, but also of the patient's health, mental status, social relations, and the improvement of the tumor related symptoms, especially for the late swelling of the tumor, the weakness of the body, and the inability to tolerate active anti tumor treatment. NSCLC patients who are treated with a one-sided pursuit of the size of the tumor are obviously unwise, and the quality of life is of great significance. Cellular immunotherapy has the characteristics of high safety and small side effects, which can be applied to advanced cancer patients and improve the patient's quality of life. Therefore, this study carries out pulse dispersion plus subtraction combined with DC-CIK for advanced NSCLC patients. Cell immunotherapy, with the quality of life as the evaluation index, the patients with advanced NSCLC, especially after radiotherapy and chemotherapy, are very easy to appear Qi Yin deficiency syndrome type. After long-term clinical practice of traditional Chinese medicine, it has been proved that Shengmai Powder has good effect on Nourishing Yin and nourishing Yin, adding and reducing Chinese medicine of removing stasis and detoxification, and the symptoms of two deficiency syndrome in late NSCLC Qi Yin. The improvement has obvious effect, the pathological nature of Qi and yin deficiency in some patients is also obviously improved, and the quality of life of the patients is improved. Objective: the 1. subject is to study the effect of pulse scatter plus subtraction combined with DC-CIK cell immunotherapy on the quality of life and TCM syndrome in late NSCLC patients, and analyze the quality of life scale based on the theory of traditional Chinese Medicine To provide evidence-based medical evidence for the establishment of a scientific and effective combination of Chinese and Western medicine for the treatment of NSCLC and clinical evaluation methods, and to explore the changes and significance of auxiliary T cell 17 (Th17 cells) in the treatment of malignant tumors by adding or decreasing the pulse dispersion combined with DC-CIK cell immunotherapy for the patients. The immune function status evaluation provided new ideas. Methods: 1. clinical trials were included in 60 cases of NSCLC Qi Yin two deficiency syndrome patients, divided into positive control group, 15 cases, pure DC-CIK cell immunotherapy, 30 cases of traditional Chinese medicine control group, giving Shengmai Powder plus or minus Decoction of traditional Chinese medicine, 15 cases in the combined treatment group were given above. Two methods combined treatment. The KPS score of 3 groups of patients before and after treatment: quality of life score, including the core 30 questionnaire survey (QLQ-C30) for the quality of life of the European cancer research and treatment organization (EORTC), and the common scale (QLASTCM-GM) for the quality of life evaluation system of malignant tumor based on traditional Chinese medicine (TCM); TCM syndrome score and immune function A comparative analysis of the relationship between QLASTCM-GM and QLQ-C30 and the correlation of TCM syndrome score in the 2. experimental study included 30 cases of Qi and yin deficiency type malignant tumor, 15 cases in the treatment group were treated with Shengmai San combined with DC-CIK immunotherapy, and 15 cases in the control group were treated with DC-CIK cell immunotherapy (2 cases), and 8 cases were included in the healthy people. Th17 cells in the peripheral blood of patients and healthy people were detected by flow cytometry. Results: 1. QLQ-C30 was used to evaluate the quality of life of patients with advanced NSCLC. Both Chinese medicine and cell immunotherapy could improve the body function score, improve the fatigue symptoms and improve the quality of life of the patients. The difficulty is better than the cell immunotherapy. Cell immunotherapy improves the quality of sleep of the patients better than the traditional Chinese medicine treatment.2. application QLASTCM-GM evaluation of the quality of life, the group comparison in the field of physique and God, the combined treatment group is higher than the traditional Chinese medicine control group (P = 0.020); in group comparison, after treatment, the quality of life before treatment is improved. There was no statistical difference between the two groups in the corresponding field, but there was a statistical difference between the Chinese medicine control group and the combined treatment group before and after treatment (P0.05). Therefore, it was concluded that after the combination of traditional Chinese medicine treatment, we can better improve the quality of life of the patients with.3. TCM syndrome score, and the clinical benefit of the combined treatment group is better than that of the traditional Chinese medicine control group, P0.05, Statistical difference.4. TCM syndrome score and QLASTCM-GM scale have a moderate correlation in the field of form and God; and the QLQ-C30 scale is only in fatigue, dyspnea, and insomnia, there is a correlation trend in the.QLASTCM-GM scale and the QLQ-C30 scale and the body function area of the QLQ-C30 scale.5. Qi and yin deficiency type malignant tumor The expression level of Thl7 in peripheral blood of patients was higher than that in healthy adults. After cell immunotherapy, the expression of Th17 in peripheral blood decreased. The expression level of Th17 in the treatment group decreased more than that of the control group. Conclusion: 1DC-CIK cell immunotherapy can improve the quality of life of late NSCLC patients with deficiency of two types of Qi and Yin. The evaluation of the quality of life of the same effect.2.: compared with the QLQ-C30 scale, the QLASTCM-GM scale is more related to the TCM syndrome score. It is worth further studying that the.3.Th17 cell is the product of the immune disorder of the patients with malignant tumor. The expression level of Shengmai Powder Combined with cell immunotherapy is obviously decreased, which indicates that the immune function state of the patients is determined by the same level. The established value may become a new indicator for evaluating immune function after immunotherapy.
【学位授予单位】：北京中医药大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R734.2

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