氩氦刀联合中药治疗Ⅲb期～Ⅳ期非小细胞肺癌的临床研究

【作者】 姜敏；

【导师】 胡凯文；

【作者基本信息】 北京中医药大学 ， 中西医结合内科学， 2014， 博士

【摘要】 目的：本课题采用回顾性的研究方法,通过对126例经过氩氦刀联合中药治疗的晚期(Ⅲb期～Ⅳ期)非小细胞肺癌患者的随访资料进行统计分析,总结其规律,分析肺癌局部微观辨证的特点及氩氦刀冷冻治疗的中医机理,为氩氦刀联合中药临床应用提供一定的临床依据及指导,评估“氩氦刀+中药”这一绿色治疗模式对晚期非小细胞肺癌患者的临床治疗价值,对其治疗时机进行优化,努力为晚期肺癌患者提供更加成熟的治疗方案。方法：采用回顾性的研究方法总结2003年9月至2013年5月在东方医院肿瘤科住院行氩氦刀冷冻联合中药治疗的Ⅲb期～Ⅳ期原发性非小细胞肺癌患者126例,分析其肺部肿瘤特点及氩氦刀冷冻治疗影像资料,研究肺癌局部微观辨证的特点及氩氦刀冷冻治疗的中医机理,并对患者生存期进行分析；另设健康对照30例,对其外周血免疫指标进行对比研究,以对这一方案治疗晚期非小细胞肺癌患者的临床价值进行评估。研究结果：[1]患者耐受情况126例Ⅲb期～Ⅳ期NSCLC患者顺利完成手术,并接受了较长时间的中医药治疗,无术中死亡病例,术中术后并发症轻微、恢复快。[2]生存期、生存率分析：①总体情况：126例患者治疗后中位生存期12个月,总中位生存期18个月。②生存率情况：126例患者冷冻治疗后随访6月、12月、18月、24月、36月生存率依次是69.8%(88/126)、42.9%(51/119)、26.8%(30/112)、12.7%(14/110)、5.6%(6/108)；自确诊起6月、12月、18月、24月、36月总生存率依次是91.3%、71.3%、48.3%、31.6%、13.5%。③从年龄角度来看：年龄<65岁患者术后中位生存期9个月、总中位生存期15个月；年龄≥65岁患者术后中位生存期14个月、总中位生存期22个月,术后中位生存两者存在显著性差异(p=0.013)。老龄患者更倾向于首选微创、低毒的治疗方案,看似保守的选择反而使其生存期获益。④从病理角度来看：80例腺癌患者术后中位生存期11个月,总中位生存期17个月；30例鳞癌患者术后中位生存期8个月,总中位生存期19个月；两组无统计学差异(术后p=0.213,总p=0.838)。⑤从TNM分期角度来看：40例Ⅲb期患者术后中位生存期14个月,总中位生存期25个月；86例Ⅳ期患者术后中位生存期8个月,总中位生存期17个月。Ⅲb期患者确实较Ⅳ期患者有更好的生存期,两者存在显著性差异(术后p=0.029；总p=0.045)。⑥从原发肺癌病灶位置来看：56例中央型肺癌患者术后中位生存期9个月,总体中位生存期17个月；70例周围型肺癌患者术后中位生存期12个月,总体中位生存期20个月。虽然两者差异并不显著(术后p=0.238；总p=0.367),但从数据上来讲,晚期周围型肺癌生存期表现较中央型要好一些。⑦从冷冻靶病灶大小角度来看：13例≤3cm者术后生存期23个月,总生存期29个月；53例3-5cm者术后生存期14个月,总生存期22个月；42例5-8cm者术后生存期7个月,总生存期15个月；18例≥8cm者术后生存期7个月,总生存期14个月。对于负荷小于5cm的肺癌患者来讲,其治疗后生存期、总生存期均明显优于大于5cm肿瘤负荷患者,存在显著差异(p<0.05)。⑨从治疗时机的角度来看：46例患者确诊后确诊后1个月内入住我院行氩氦刀联合中药治疗的患者,术后中位生存期13个月,18例2-3个月治疗者术后中位生存期12个月,9例4-6个月者治疗后中位生存期10个月,53例>6个月者术后中位生存期9个月(P>0.05)。[3]冷冻比率分析94例患者可以对术中瘤灶的冷冻比率评价。8例瘤灶≤3cm的患者平均冷冻比率98.5%,37例瘤灶3-5cm的患者平均冷冻比率85.0%,33例瘤灶5-8cm的患者平均冷冻比率73.7%,16例瘤灶≥8cm的患者平均冷冻比率49.6%。病灶越小,冷冻比率越高,冰球完全覆盖肿瘤达到局部病灶根治性冷冻的可能性越大。94例患者中,中央型肺癌55例,平均冷冻比率73.2%；周围型肺癌39例,平均冷冻比率84.8%。11例心脏大血管受侵患者平均冷冻比率64.8%：13例患者大面积肺不张,平均冷冻比率69.1%。周围型肺癌较中央型肺癌冷冻比率更高。20例冷冻比率≤50%的患者术后中位生存期8个月；23例冷冻比率在50%-80%的患者术后中位生存期6个月；28例冷冻比率80%-100%的患者术后中位生存期14个月；23例冷冻比率≥100%的患者术后中位生存期18个月。冷冻比率越高患者生存获益越明显。[4]氩氦刀时机的选择无论是初治时还是疾病进展以后选择氩氦刀冷冻治疗,都能使患者治疗后生存期获益,但患者术后生存曲线提示,晚期肺癌患者越是早期采用氨氦刀联合中药治疗,其术后生存获益可能越明显。[5]晚期肺癌患者免疫状态126例患者中38例在冷冻联合中药治疗前检测了外周血T细胞亚群、NK细胞,与30例健康患者外周血T细胞及NK细胞水平比较显示：晚期肺癌患者外周血CD4+比例降低(p=0.003),而CD8+水平升高(p=0.010),统计学存在显著差异。表明晚期肺癌患者免疫功能相对较差,或者处于免疫抑制的状态。提示临床可能需要增强免疫治疗。而21例患者冷冻治疗前后外周血免疫指标对比无明显差异,提示氩氦刀冷冻治疗短期内并未改变患者的免疫功能。[6]肺癌的局部微观辨证综合文献及借助于现代影像技术,肺癌局部病变“红”“肿”“热”特征明显,加之其无限增生、侵袭性、转移性无不揭示着其异常的阳动之性,其局部肿瘤处于明显的阳热证状态,热毒亢盛。[7]氩氦刀冷冻治疗肺癌的中医机理氩氦刀治疗肺癌法以“热者寒之”,使阴寒之法直达热邪之所,从而使有形之热邪最终得以消散于无形。氩氦刀冷冻的治疗肺癌是辨证治疗。结论：[1]氩氦刀联合中药治疗NSCLC安全有效,可以使IIIb-IV期患者生存获益。[2]“氩氦刀+中药”模式是基于短期快速减轻肿瘤负荷、长期绿色低毒体质调理的可持续的治疗思路,可以作为IIIb期～IV期肺癌患者治疗的主要方案。[3]肺癌局部微观辨证是阳热毒邪,氩氦刀形成的冰球性“寒”；法以“热者寒之”,采用氩氦刀冷冻治疗肺癌是对“证”治疗,是辨证治疗,切实可行。[4]晚期肺癌患者免疫功能降低,临床治疗应当增强免疫治疗。[5]本课题提出了冷冻比率的计算方法,研究显示提高冷冻比率有利于使患者临床生存获益。更多还原

【Abstract】 Objective:A retrospective clinical study was carried out on126advanced (Ⅲb-IV) non-small cell lung cancer (NSCLC) patients who accepted the therapy of cryosurgery combined with TCM, to analyze local microdialectics characteristic of lung cancer and TCM mechanism of cryosurgery therapy, which can provide clinical evidence and guidance, furthermore, to evaluate the clinical value of the "Cryosurgery-TCM" green therapy model, optimize cryosurgery and provid a mor perfect therapy for advanced lung cancer patients.Methods:126advanced NSCLC patients who accepted cryosurgery-TCM therapy during September2003to May2013in oncology department, Dongfang hospital, were enrolled in this study. The clinical data, including lung cancer characteristic, cryosurgery related image data, local microdialectics characteristic of lung cancer and TCM mechanism of cryosurgery were collected in order to analyze survival time of different patients. Meanwhile,30relative normal control cases were also enrolled. Peripheral immune status was compared between the two groups. Then clinical value of the cryosurgery-TCM therapy model was evaluated on advanced NSCLC patients.Results:[1] Patients’ endurance summaryAll the126NSCLC patients underwent cryosurgery successfully and received TCM therapy for long time. During ablation no death occurred. The complications during and after ablation were mild and revovered fast.[2] Survival rate analysis①General description:For the total126patients, the median survival time was12months and the overall survival time was18months.②Survival rate description:The survival rates were69.8%(88/126),42.9%(51/119),26.8%(30/112),12.7%(14/110) and5.6%(6/108) at the time of the6th,12th,18th,24th and36th months after cryosurgery, respectively. When calculating from the date of NSCLC diagnosis, the survival rates were91.3%,71.3%,48.3%,31.6%and13.5%correspondingly.③Survival analysis based on incident age:Younger patients (<65years old) achieved15months overall survival time and9months after-cryosurgery survival time, while older patients (≥65years) achieved22months overall survival time with14months after-cryosurgery survival time. Significant difference was observed of after-cryosurgery survival time (p=0.013). The elder tended to accept conservative choice of minimal invasive and less toxic therapy, Which gained a better survival benefits.④Survival analysis based on pathology: 80adenocarcinoma lung cancer patients, achieved17months overall survival time and11months median survival time. While30squamous cell carcinoma lung cancer patients, achieved19months overall survival time with8months median survival time (after-cryosurgery p=0.213,overall p=0.838). There were on significant differences between the two pathologic types.⑤Survival time based on TNM stages:For the40Ⅲb phase patients, they got25months survival time and14months median survival time. Eighty-six IV stage patients gained17months overall survival time and8months median survival time. Ⅲb stage patients had a longer survival time (after-cryosurgery p=0.029, overall p=0.045)⑥Survival time based on primary lung cancer locations:56central lung cancer patients had17months overall survival time and9months median survival time, meanwhile,70peripheral lung cancer patients had20overall survival time and12months median survival time (after-cryosurgery p=0.238, overall p=0.367).Advanced peripheral lung cancer patients had more advantages when accepted this therapy model.⑦Survival time based on target cryo-lesions size:There were13、53、42and18patients whose target cryo-lesions size were≤3cm,3-5cm、5～8cm and≥8cm, respectively. Their overall and median survival times were29、22、15、14months and23、14、7、7months correspondingly. The more tumor load, the shorter survival time was.(p<0.05)⑧Survival time based on therapy time points:According to the time points, there were46,18,9and53patients suffering from lung cancer for1,2～3,4～6and>6months when patients accepted cryosurgery, respectively. Their median survival times were13,12,10and9months correspondingly(P>0.05).[3]Lesion cryoablation coverage rate analysis:Lesion cryoablation coverage rate was evaluated in94patients. There were8,37,33and16patients with≤3cm,3～5cm,5～8cm and≥8cm lung cancer cryo-lesions. Their mean cryoablation coverage rates were98.5%,85.0%,73.7%and49.6%, respectively. The higher cryo-coverage rate can be found in small size lesions.In the94patients,55patients were central lung cancer and39patients were peripheral lung cancer. Their mean cryo-coverage rates were73.2%and84.8%, respectively. The mean cryo-coverage rate in11patients with heart vascular invasion was64.8%which that in13patients with large areas of atelectasis was69.1%. Higher cryo-coverage rate can be seen in peripheral lung cancer patients than that in central lung cancer patients.The association between cryo-coverage rate and survival time was analyzed. There were20,23,28and23patients with≤50%,50%-80%,80%-100%and≥100%cryo-coverage rate. Their median survival times were8,6,14and18months. Patients who got higher cryo-coverage rate gained a longer survival time.[4]Cryosurgery time analysis:The patients who received cryosurgery can have a longer survival time in the period of initial treatment or disease progression. However, advanced lung cancer patients who accepted cryosurgery-TCM earlier would get more benifits.[5]Immune status analysis:Peripheral blood was got from38lung cancer patients and30relative mormal control cases. The amounts of T cells, NK cells were tested. CD4+cell ratio in peripheral blood decreased (p=0.003), while CD8+cells ratio increased significantly (p=0.010). Advanced lung cancer patients had a relative bad immune function or were in immunosuppression status. Which means the cryosurgery didn’t change immune function in the short time.[6] Local micro dialectics characteristic analysis:According to documents and morden image technology, the features, such as "red","swollen","hot" and "pain", were obvious. Meantime, the lung cancer had "Yang" features, such as unlimited growth, invasion and metastases, which showed the local tumor belonged to toxic heat syndrome.[7] TCM mechanism of cryosurgery application for lung cancer:A principle for lung cancer cryosurgery application is "treating hot syndrome with cold natured drugs", which is a classic TCM theory. TCM theory indicates that the solid tumor of a "hot" feature can disappear if the "cold" can reach. The cryosurgery for lung cancer is a differential treatment.Conclusion:[1] It is safe and effective for advanced NSCLC patients (stage Ⅲb-Ⅳ) who accept cryosurgery plus TCM therapy.[2] Cryosurgery plus TCM therapy model is a new and promisingstrategy for advanced NSCLC patients (stage IIIb-IV), and it can decrease tumor load rapidly and sequential low toxic green TCM therapy providing the possibility for patients" physique adjustment.[3] It is feasible to treat lung cancer with cryosurgery therapy based on local lung cancer micro dialectics characteristic. The ice ball forming during cryosurgery therapy is "cold", and it matches with "hot" of local lung cancer. It can be clarified by TCM principle "treating hot syndrome with cold natured drugs".[4] The immune function should be enhanced for advanced lung cancer during our clinical practice.[5] The method of lesion cryo-coverage rate was established, higher cryo-coverage rate of lung cancer is useful for better survival time.更多还原