【作者】 曹敏；

【导师】 周岱翰；

【作者基本信息】 广州中医药大学 ， 中西医结合临床， 2011， 博士

【摘要】 肺癌发病率、死亡率高,发现时多为晚期。传统治疗包括手术、放疗、化疗等局限性日渐凸显,分子靶向药物作用不确切。多学科综合治疗模式是肺癌治疗的方向。中药治疗肿瘤已体现出“带瘤生存”的优势,但近年来中药治疗肺癌疗效没有大的突破。为进一步提高疗效,探讨中医综合治疗模式,有必要进行针灸治疗肿瘤的相关研究。针灸具有良性、双向性、整体性的治疗特点,临床观察发现针灸对肿瘤的疗效,尤其在改善症状、减轻放化疗副反应、增加放化疗效果方面作用确切,且副反应小、费用低廉。通过文献回顾发现目前的研究存在诸多问题,如不少文献无对照；部分国内文献缺乏客观的诊断标准；临床研究方法及治疗方案不规范；样本量少；疗效评价标准差异大等等,造成结果可信度较低。本研究拟通过客观科学的临床及实验研究,观察针灸在NSCLC治疗中的意义,并探讨其部分作用的机制。1针灸在NSCLC临床治疗中的作用[目的]通过前瞻、对照的临床研究,观察并分析针灸对中晚期NSCLC患者的疗效指标、安全性指标的影响,探讨针灸对NSCLC肺癌临床症状、生存质量、体力状况评分、化疗副反应、理化指标等方面的作用。[方法]本研究病例来自广州中医药大学第一附属医院、广东省中医院、广州市中医医院、佛山市中医院等四家医院在2008年9月-2011年3月期间Ⅲ-Ⅳ期NSCLC住院及门诊患者,共205例。根据病情及患者意愿进行分组治疗。其中中药治疗组48例,中药针灸治疗组61例,中药化疗组45例,针药化疗组51例。中药治疗组采用辨病与辨证相结合的治疗方法。辨病治疗包括口服清金得生片和参一胶囊；辨证分型治疗按肺郁痰瘀、脾虚痰湿、阴虚痰热、气阴两虚四种分型加用汤剂治疗。21天为一疗程,共两疗程。中药针灸治疗组为针刺及敷贴治疗+中药治疗,穴位处方为肺俞、膏肓、膈俞、胆俞、足三里(均双侧)。治疗21天为一疗程,共两疗程,采取疗程前5天针灸治疗,后16天穴位敷贴治疗的方法；中药化疗组为化疗+中药治疗,化疗方案为含铂类方案,可选用NP/GP/DP方案或选用多西他赛或培美曲塞治疗。每21天重复,共2个周期；针药化疗组为针刺及敷贴治疗+化疗+中药治疗,同时采用上述三组的治疗。主要疗效指标是症状改善、体力状况评分、生存质量,化疗副反应改善、肿瘤缓解等。[结果]在肿瘤缓解上：有效率分别为中药组4.17%,中药针灸组4.92%,中药化疗组24.44%,针药化疗组27.45%；稳定率分别为中药组56.25%,中药针灸组59.02%,中药化疗组75.56%,针药化疗组86.27%。中药化疗组与针药化疗组的肿瘤缓解情况均都比中药组或中药针灸组更好,有统计学意义；针药化疗组与其他三组的肿瘤稳定率比较,有显著性差异。在临床症状评分方面：各组治疗前后自身比较均有明显的改善(F=8.851,P=0.000<0.05)；针药化疗组疗效较其他三组更好；中药化疗组次之,与中药组及中药针灸组比较有统计学意义。在PS评分上：四组治疗前后自身比较,均有不同程度的改善,其中针药化疗组较其他三组改善更明显(P<0.05),中药化疗组次之,与中药组及中药针灸组比较有统计学意义。在生存质量评分方面：各组生存质量积分治疗后比较：中药针灸组、中药组治疗后较治疗前自身对照均有明显升高,中药针灸组较中药组更高,但两者之间没有统计学意义；中药化疗组及针药化疗组治疗后对比治疗前评分下降,中药化疗组比针药化疗组下降更明显,但无显著性差异；中药针灸组在情绪状况领域、功能状况领域以及肺癌关注情况方面较中药组改善更明显,有统计学意义。另外,针灸对不同证型的患者的生存质量评分均有提高,以脾虚痰湿组最为明显,有统计学意义。在对化疗副反应的作用方面：除口腔炎/咽炎对比治疗前无显著性差异外,其他各项症状体征得分均有上升,有统计学意义。中药化疗组在恶心呕吐、腹泻及便秘等症状上较针药化疗组得分升高更明显；针药化疗组在瘙痒症状上较中药化疗组得分升高更明显。在血象方面：中药化疗组、针药化疗组PLT、PLT下降较中药针灸组或中药组明显,有统计学意义；中药化疗组PLT、PLT下降较针药化疗组更明显,有统计学意义；中药针灸组的WBC较中药组升高更明显。在肿瘤标志物方面：四组CEA、CA125、CA199治疗后较治疗前自身对比,均有显著性下降；中药化疗组、针药化疗组CEA、CA199均较中药针灸组和中药组下降明显,有统计学意义；针药化疗组能使CA125下降更多,与其他三组有显著性差异。在治疗安全性方面,并未发现有因针灸而导致的心肝肾功能的损害,小部分的患者出现皮下出血、轻度疼痛等情况,较多见的副反应为穴位敷贴部位皮肤潮红、瘙痒等。经对症处理后症状可减退,可以继续治疗。整体而言,针灸治疗具有较好的安全性。[结论]在中药基础上配合针灸治疗中晚期NSCLC,较单用中药治疗,在稳定血象、改善生存质量,尤其是情绪状况领域、功能状况领域以及肺癌关注情况等方面有更大的优势；化疗、中药联合针灸治疗较化疗配合中药治疗在改善肺癌症状、降低PS、稳定肿瘤、减少化疗副反应、减少WBC下降等方面效果更好,并能使CA125下降更多；根据肿瘤稳定率、症状改善情况、肿瘤相关指标等综合评价,可以判断针灸对化疗具有一定的增效作用；综合评价症状改善情况、PS评分、血象、化疗副反应等方面,判断针灸对化疗具有一定的减毒作用。另外,针灸对不同证型的肺癌患者生存质量均有较好的改善,而对脾虚痰湿型患者效果最明显。根据肿瘤稳定率、症状改善、PS评分改善、肿瘤指标降低等方面综合评价,包括中药、针灸、化疗等方面的中医综合治疗,在中晚期非小细胞肺癌治疗上较单用中药或中药+针灸或中药+化疗具有更大的优势。针灸在中晚期肺癌治疗中的作用明显,无明显副反应,值得临床推荐。2针灸治疗荷Lewis肺癌小鼠的实验研究[目的]通过动物实验,建立荷Lewis肺癌小鼠模型,观察针灸对荷Lewis肺癌小鼠的治疗作用及其部分作用机制。[方法]60只小鼠随机分为4组,每组15只,分别为荷瘤空白组,荷瘤针灸组,荷瘤化疗组,荷瘤化疗针灸组。首先建立Lewis肺癌动物模型。先将液氮冻存的小鼠Lewis肺癌小鼠细胞复苏后,先接种于4只C57BL/6小鼠右腋窝皮下,制备传代荷瘤鼠。传3代后处死小鼠,在无菌条件下剥取荷瘤小鼠瘤块,制备成5×106/ml肿瘤细胞悬液。每只小鼠右侧腋窝皮下接种0.2ml肿瘤细胞悬液。接种后第二天开始治疗,荷瘤化疗组参照张素胤用量(1mg/kg),以DDP溶液0.1ml/20g每日腹腔注射1次,连续10天；荷瘤针灸组取肺俞(双侧交替)、足三里(双侧交替),用30号毫针(0.5寸),常规消毒后直刺0.2-0.3寸,留针5分钟,每日一次,早上10时执行,连续10天；荷瘤化疗针灸组采用荷瘤化疗组及荷瘤针灸组的治疗。[结果]连续治疗10天后存活小鼠空白组15只,针灸组14只,化疗组12只,针灸化疗组12只。治疗期间死亡率化疗组、针灸化疗组较空白组、针灸组更高,有统计学意义；化疗组较针灸化疗组更高,有统计学意义。瘤体重量比较：空白组为3.25±0.26g,针灸组为2.84±0.41g,化疗组为2.37±0.47g,针灸化疗组为2.03±0.27g；针灸组、化疗组、针灸化疗组抑瘤率分别为12.58%、27.07%、37.41%；针灸组瘤重与化疗组、针灸化疗组比较,差异均有统计学意义；化疗组与针灸化疗组比较,差异有统计学意义。各组去瘤体重比较：以针灸组最重,其次为空白组、针灸化疗组,化疗组最轻,但四组间差异无统计学意义。免疫器官重量比较：脾重分别为空白组0.20±0.03g,针灸组0.27±0.06g,化疗组0.18±0.03g,针灸化疗组0.26±0.05g；针灸组与空白组比较,有统计学意义；针灸化疗组与空白组、化疗组比较,有统计学意义。胸腺重量针灸组最重,但四组间无显著性差异。细胞因子水平比较：血清TNF-α,分别是空白组2.00±0.24ng/m1,针灸组1.96±0.45ng/ml,化疗组2.38±0.28ng/ml,针灸化疗组2.31±0.30ng/ml；TNF-α水平以化疗组最高,其次为针灸化疗组；化疗组、针灸化疗组分别与空白组、针灸组比较均有显著性差异；化疗组和针灸化疗组之间,空白组和中药针灸组之间,均无显著性差异。血清IL-6,分别为126.13±22.85pg/ml,针灸组84.48±15.03pg/ml,化疗组110.78±15.25pg/ml,针灸化疗组90.95±14.72pg/ml；空白组最高,较其他三组有显著性差异；针灸组最低,其次为针灸化疗组,针灸组与化疗组之间有显著性差异,针灸组和针灸化疗组之间无显著性差异。[结论]针灸治疗对荷瘤小鼠具有一定的抑瘤作用,其作用虽不及化疗明显,但如针灸能联合化疗则较单纯针灸或化疗更能抑制肿瘤进展。该结果与本研究的临床研究结果基本相符,进一步体现中西医综合治疗肿瘤的优势。针灸可增加免疫器官(脾)的重量,减轻肿瘤及化疗对免疫功能的损害,具有一定的免疫保护作用,可能是针灸抗肿瘤的机制之一。TNF-α与IL-6水平均可作为监测肺癌病程进展、治疗效果以及疾病预后的辅助指标,同时也与肿瘤导致的虚证密切相关。中医认为,肿瘤产生的基础是正虚,正虚与肿瘤形成及其病机演变、预后等皆有密切关系,而中晚期肺癌多因虚致病,因病致虚,辨证多为虚中夹实或虚实夹杂,肺癌化疗后尤多见脾肾亏虚。因此,扶正补虚是中晚期肺癌的重要治疗原则。针灸具有扶正培本的作用,能明显改善虚证。本研究表明,针灸治疗具有显著降低血清TNF-α和IL-6浓度的作用,提示针灸可能是通过改善肺癌的虚证而达到治疗目的,该作用可能是针灸治疗肺癌产生疗效的重要因素之一。此外,针灸安全性较好,未见明显副作用。更多还原

【Abstract】 The incidence rate and the death rate of the lung cancer is very high, most of the patients are on the advanced stage when they are diagnosed. The conventional therapy of lung cancer including the operations、radiotherapy and the chemotherapy has its limit, the effect of the targeted drugs is not certain. The mode of combined therapy is the trend of the treatment of lung cancer. TCM has showed up the superiority of "living with the tumor", but the curative effect are similar in recent years. The acupuncture and moxibustion has the characteristic of innocuousness、ambidirectional dominance and entirety, so it works in the treatment of lung cancer, especially improving symptoms、easing the side effects and raising the curative effect of the radiotherapy and the chemotherapy, and it has little side effect and it charges little. There are many problem in the study and research of the acupuncture and moxibustion, as some of them have no control groups, some have no standard diagnostic criteria、treatment perscription and the evaluation criterion, some have small sample size, and it made the result not confident.This article is about the analysis of curative effect of acupuncture and moxibustion including quality of life、symtoms、side effects of chemotherapy etc in nonsmall-cell lung cance (NSCLC) based on the perspective and control study;and trys to analyse the impact on the of mouse with lung cancer of acupuncture and moxibustion.1 The analysis of curative effect of acupuncture and moxibustion in NSCLC based on the clinical research. OBJECTIVE:Observe the curative effect of acupuncture and moxibustion including quality of life、symtoms、side effects of chemotherapy etc in nonsmall-cell lung cance (NSCLC) based on the perspective and control study.METHODS:From Sep,2008 to Mar,2011,205 patients, with NSCLC in stageⅢ-Ⅳ, were recruited in four hospitals including The 1st affiliated hospital of Guangzhou University of TCM, The 2nd affiliated hospital of Guangzhou University of TCM, Guangzhou Hospital of TCM and Foshan Hospital of TCM.48 cases in group TCM(group T),61 cases in group integrated acupunture with TCM (group A+T),45 cases in group integrated chemotherapy with TCM (group C+T), and 51 cases in group integrated acupunture, chemotherapy with TCM(group A+C+T).Project for group TCM:with combination of syndrome differen-tiation and disease differentiation, Qingjingdesheng tablets and Shenyi capsules were used according to disease differentiation, and different decoctions were determined from four patterns:phlegmatic stagnation due to passive congestion of lungs (FYTY), phlegmatic hygrosis due to spleen asthenia(PXTS), yin-deficiency and phlegmopyrexia(YXTR) and deficiency ofboth qi and yin(QYLX) according to syndrome diffentiation, and the period of treatment was two courses,21days per course. Project for group integrated acupunture with TCM:the treatment of TCM is the same as group TCM. both Lung Shu, Vital Organs, Diaphragm Shu, Gallbladder Shu and Foot Three Li were chosen in the acupunture therapy, the period of treatment was two courses,21days per course. The first 5 days needling and the last 16 days point application. Project for group integrated chemotherapy with TCM:Platinum-based chemotherapy were used besides the treatment of TCM, either NP/GP/DP regimen or Docetaxel/pemetrexed was adopted, and were repeated every 21days, two times. Project for group integrated acupunture, chemotherapy with TCM:the treatment is the same as the last three groups. The primary points was symptoms improvement, survival, quality of life, side effect of chemotherapy improvement, tumor response rate, ECOG.RESULTS:Tumor response rate(CR+PR) were 4.17% of group TCM,4.92% of group A+T,24.44% of group C+T,27.45% of group A+C+T;The disease control rate were 56.25%of group TCM,59.02% of group group A+T,75.56% of group of group C+T,86.27% of group A+C+T. There were statistical significance between group T/ A+T with group C+T/ A+C+T; there were statistical significance between group A+C+T and the other groups in the disease control rate.Symptoms scales changes after treatment of four groups compared:there were statistical significance between group A+C+T and the other groups, there were statistical significance between group C+T and the group T/ A+T.PS scales decrease after treatment of four groups compared:there were statistical significance between group A+C+T and the other groups, there were statistical significance between group C+T and the group T/ A+T.The quality of life changes after treatment of four groups compared: group A+T and group T inproved after the treatment, but group C+T and group A+C+T decreased after the treatment. There were statistical significance between the group A+T and the group T in the emotional condition funtional condition and lung cancer information. And acupunture works for all types of syndrome, especially for the patients who have got phlegmatic hygrosis dueto spleen asthenia(PXTS).Most of the side effect scales worsened after the treatment of group C+T and group A+C+T. Refers to the symtoms like nausea and vomitting、diarrhoea constipation and pruritus, there were statistical significance between group C+T and group A+C+T.WBC and PLT scales changed after treatment of four groups compared: there were statistical significance between group T/ A+T and other two groups, there were statistical significance between group A+C+T and group C+T, there were statistical significance between group A+T and the group T.CEA、CA125、CA199 decreased after the treatment of four groups;CEA、CA199 in group C+T、group A+C+T decreased more than group A+T and group T. Group A+C+T was the lowest, and there were statistical significance between group A+C+T and the other three groups.The heart function、Hepatic function and renal function of the patients has not getten worse after the acupumture therapy. Some patients got subcutaneous hemorrhage、pain after the treatment. The common side effects were erubescence and pruritus. The side effects could be cured, and so the acupumture therapy is safe.CONCLUSI ONS:The treatment integrated acupumture with TCM is better at stabilizing hemogram、improving the quality of life such as emotional condition functional condition and lung cancer imformation than TCM. The treatment integrated chemotherapy、acupumture and TCM is better at improving the sympton、decreasing PS、stabilizing hemogram、increasing the disease control rate、decreasing the side effect of chemotherapy and decreasing CA125 than the treatment integrated chemotherapy and TCM. According to the disease control rate、symptoms improvement tumor markers, acupumture can elevate the effect of chemotherapy. According to the symptoms improvement PS decrease、hemogram、side effect of chemotherapy, acupumture can degrade the toxicity of chemotherapy. And acupunture works for all types of syndrome, especially for the patients who have got phlegmatic hygrosis dueto spleen asthenia(PXTS).According to the disease control rate、symptoms improvement、PS decrease and tumor markers, the treatment integrated chemotherapy、acupumture with TCM is the best way to cure NSCLC. And acupumture is very safe.2 The Experimental Research of acupumture in Treatment of Lewis Lung Cancer(LLC) MiceOBJECTIVE:To analyse the effect of acupuncture and moxibustion on the mice with lung cancer.METHODS:60 C57BL/6 mice were randomly divided into four groups, there were15 mice each group, and four groups as follows:LLC blank (group A), LLC acupumture (group B), LLC chemotherapy(group C) and LLC acupumture and chemotherapy(group D).Step 1:After awaking LLC cells to be frozen by liguid nitrogen, four C57BL/6 mice’right axilla subcutaneous part were inoculated by LLC cells 2.5×105, for establishing transfer of culture LLC mice. The mice were killed after transfer to three generation, and tumor was taken in sterile to make tumor cell suspension which concentration was 5×106/ml. Every mouse’right axilla subcutaneous part was inoculated by 0.2ml tumor cell suspension. On the second day Post inoculation, treatment began. In group B, Both Lung Shu, Foot Three Li were chosen in the acupunture therapy, and every day for 10 days.Group C were administrated intraperitoneal cisplatin by 0. lml/20g every day for 10 days. Group D took the same treatment with group B and group C.RESULTS:After continues treatment for ten days, survival mice number of group A, B, C and D were 15,14,12 and 12 respectively。The death rate of group C and D is higher than group A and B, and group C is higher than group D. Weight of tumor of group A, B, C and D were 3.25±0.26g,2.84±0.41g,2.37±0.47g and 2.03±0.27g respectively;There were statistical significance between group B and group C or D; there were statistical significance between group C and D. Suppress tumor rate of group B、C and D were 12.58%、27.07%、37.41% respectively. Body weight except tumor of group compared:group B is the heavest, but there was no statistical significance between groups.Weight of spleen of group A, B, C and D were 0.20±0.03g,0.27±0.06g, 0.18±0.03g and 0.26±0.05g respectively;Weight of thymus gland of group A, B, C and D were 0.055±0.016g,0.036±0.015g,0.031±0.008g and 0.045±0.012g respectively;there were statistical significance between group A and group B; there were statistical significance between group D and group A or C. Weight of thymus gland compared:group B is the heavies, but there was no statistical significance between groups.Serum TNF-αlevel of group A, B, C and D were 2.00±0.24ng/ml,1.96±0.45ng/ml,2.38±0.28ng/ml,2.31±0.30ng/ml respectively;there were statistical significance between group C/D and group A/B, but there was no statistical significance between group A and B or C and D. Serum IL-6 levels of group A, B, C and D were 126.13±22.85pg/ml,84.48±15.03pg/ml, 110.78±15.25pg/ml,90.95±14.72pg/ml respectively;there were statistical significance between group A and the other groups;there were statistical significance between group B and C.CONCLUSIONS:The treatment of acupumture could suppress tumor growth of LLC mice, which was weaker than chemotherapy, but acupumture integrated with chemotherapy would be better than acupumture only or chemotherapy only.The treatment of acupumture could increase the weight of LLC mice spleen to some extent, and enhance immune function of animal body to some extent.TNF-αand IL-6 is the index that could reflect the lung cancer aggravation therapeutic efficacy and the prognosis, and correlates to the deficient syndrome. Acupumture could decrease serum TNF-αand IL-6 levels significantly, which may be one of important reasons for treating the lung cancer.更多还原