中国冷冻消融治疗原发性肝癌的最新进展

2009年世界肿瘤介入学术大会汇编CT guided radioactive 1筋I seed implantation compared with firstlinechemotherapy in treating localized advanced pulmonaw carcinoma：acontrol studyzHANG Fu-junZHANG Liang WU Peihong HUANG Jinhua FAN Wei-jun GU Yang-kui LI Chuanxing LI Kui Lu Ming-jianDepartment of Imaging and Interventional Radiology Cancer Center Sun YatSen University Guangzhou 5 10060 ChinaAbstractObjective：To investigate the clinical value ofCT guided radioactive seed 1251 implantation(C3RISI)in the treatmentof localized advanced pulmonary carcinomaMethods：Thirtytwo patients(Group A)with localized advanced pulmonary carcinoma，received radioactive seed1”I implantation after failure in first line chemotherapyThere were 1 5 males，and 1 7 females，ageing from 3 1 to 73 yearsold520 on the averageThere were 48 lesions in the 32 patients altogether and all the lesions had a clear border with theadiacent normal tissueThe diameter of tumors was 4575cmthe average was 55cmAll the cases had been confirmed asmalignant by pathology(percutaneous aspiration biopsy)I seeds of 2加33x10 7megabecquerel(MBq)were implantedinto these lesionsThe total number of the seeds implanted in each】esion was 1 01 00The dosage of the region aroundthe tumor was 100150GyAccording to Treatment Planning System(TPS)，we implant the 125I seeds into the tumorsunder CT guidanceW-e picked 30 patients(Group B)to be treated by first line chemotherapy in our hospital randomly asthe control groupResults：The results of CT followup after two months proved that the local control rate of the group treated with125I seeds implantation was 781one year survival rate Was 650。median survival time was 15 monthsSmall amountof effusion was observed in these patients during operationPneumothorax happened in 4 cases with one of the lungscompressed less than 30 percent and got improved healthy after conservative treatmentOne week after the procedure，bloody sputum occured in l 5 casesNo myelosuppression and other serious complications occurred in these patientsThelocal control rate of the control group was 433、one year survival rate was 480，median survival time was 1l months，the incidence rate of myelosuppression is 463There was a significant difference between the two groupsConclusion：CTGRISI procedure iS safe and welltolerated in treating localized advanced pulmonary carcinoma inChinese patients with few complications；it Can improve the living quality obviously and has good shortterm effects【Key wordsIodine radioisotopes；interventional；brachytherapy；localized advanced stage pulmonary carcinoma；evaluation studies中国冷冻消融治疗原发性肝癌的最新进展张积仁史德刚南方医科大学珠江医院肿瘤中心本讲座论述了中国冷冻消融治疗肝癌的最新进展，包括6个部分：1在外国友人的帮助下。氩氦冷冻消融技术被引进中国。氩氦冷冻消融技术是20余项美国航天专利高新技术的结晶，1998年FDA批准使用。19992002年期间，美国有200家医院安装了这种设备，已经取代液氮和其它冷冻外科治疗设备。1999年，第1Nendocare冷冻外科系统在第一军医大学珠江医院使用，国际生物治疗学会主席PKLehtinen和副主席RHanka来到中国为珠江医院氩氦冷冻治疗中心剪彩。1999年，I扫Peter J Litrup，张积仁和汪森明三位教授在中国珠江医院使用Endocare冷冻外科系统完成了第1例冷冻外科手术。Endocare冷冻外科系统在中国被命名为氩氦冷冻消融(氩氦刀)。1999年，CT引导下经皮冷冻消融治疗的第l例肝癌患者是TACE术后在珠江医院完成。代表中国氩氦冷冻外科协作组，我们将非常感谢以下外国友人的帮助和指导中国发展冷冻治疗，这些教授分别是Peter JLitrrup，Suzy Chosy。Daniel Rukstalis，Andre，DPeterson，Gregory Groves，Daniel RlIkstaUs，Go Wakadayash，Winoruanabe and Dan silver，等等。Endocare冷冻外科手术系统在中国医学科学院士的指导下已经应用于肿瘤中心，他们分1102009年世界肿瘤介入学术大会汇编别是吴孟超，郝希山，汤钊猷，吴咸中。从1999-2007年，Endocare冷冻外科手术系统已经在中国的70家医院中使用。2影像引导下经皮冷冻消融的程序在DSA，CT，MR，腹腔镜，超声波引导下，冷冻消融有助于治疗实体瘤，例如肺癌，肝癌，胶质瘤，软组织肿瘤，乳腺癌，卵巢癌，骨肿瘤，胰腺癌，前列腺癌，肾癌，皮肤肿瘤，肛门直肠癌，口腔癌，宫颈上皮内瘤变，等等。使用CT，MR，PET和DSA影像学观察了靶向冷冻消融的组织，中国的几家医院报道了临床结果。肿瘤标记物例如CEA，AFP，PSA，CAl9-9在不同种类的肿瘤冷冻消融治疗前后也作了分析。3靶向冷冻消融的基础研究对于实体瘤冷冻外科有效的治疗体现在：(1)动物肿瘤模型的分析，(2)冷冻外科术后病人体内肿瘤组织的检查；(3)使用免疫学和分子生物学方法的研究。最经常使用的冷冻消融系统是美国生产的Endocare冷冻治疗系统，最近，其他的冷冻外科系统也在中国使用，例如超过10家医院使用以色列生产的Galil Medical System。另外，清华大学也生产一种液氮冷冻消融系统，另一种氮气冷冻消融系统在上海交通大学生产，这两种设备有望在20082009年的医疗市场上见到。肿瘤细胞系冷冻治疗前后的变化由几家医院报道。冷冻治疗对于正常组织的效果也在动物模型和肿瘤病人进行了观察，例如对于动脉和静脉，胆管，胰腺和支气管的效果也进行了研究。冷冻消融术后体内靶向治疗的肿瘤组织变化进行了检查并得到随访，切除的组织标本也在体外进行了分析。冷冻消融治疗的影响因素，例如冷冻消融时间，温度，血液，氩气和氦气的压力情况，穿刺针的直径，以及靶向治疗的病灶边缘也被中国医生进行了研究。治疗的有效性在临床肿瘤学领域得到验证，其标准程序也被每一个医生熟悉。并且，临床肿瘤学的DCs，TLs，NK，LAK，以及细胞因子方面的冷冻免疫学研究计划也进行了探讨，超过10家医院参加了这个项目。4靶向冷冻消融临床研究除了外科切除和介入治疗程序之外，微创外科治疗肝癌意义重大。联合化疗和冷冻治疗非小细胞肺癌；联合冷冻消融和放疗治疗250例非小细胞肺癌由宋华志报道。他们的结果显示联合冷冻治疗的效果可以延长1年和2年的生存率。联合TACE和冷冻治疗382例肝癌病人由宋华志报道，分别显示TACE的有效率328，TACE和冷冻的有效率583。在使用冷冻治疗肿瘤的过程中，中国氩氦冷冻外科协作组总结了几种肿瘤治疗技术的选择要求，包括许多方面，例如适应症，效果，毒性，并发症，对于其他治疗方法的影响，减轻疼痛，生活质量，减少心理负担，经济花费(社会家庭工作单位)。中国氩氦冷冻外科协作组呼吁生产厂家重视消融技术的临床问题，例如：靶区消融范围，立体形状，临床指南；靶区物理及生物学影响因素；微创消融治疗技术靶区的适型设计，靶向定位，靶向引导与导航；消融靶区的适时监测与靶区控制，靶区消融后近期与远期的评价标准；亚临床及残余病灶的治疗；综合治疗的选择。并且，中国氩氦冷冻外科协作组也强调了消融治疗在肿瘤治疗现代模式中的地位，他们编辑了3本冷冻治疗书籍，涉及到冷冻靶向消融治疗，肿瘤冷冻外科治疗和生物医学工程学的冷冻机制方面。自从1999年开始，中国生物医学工程学会肿瘤靶向治疗技术分会召开了靶向消融和微创治疗5次国际会议和4次国家级会议。5中国氩氦冷冻外科协作组治疗的肿瘸患者统计数目2007年11月，第14届世界冷冻治疗大会统计了中国12家医院使用美国Endocare冷冻消融系统治疗的肿瘤病人，数目达到ll，000例，其中超过500例的医院分别超过10家，部分医院病例数达到4000例。冷冻治疗了超过30种疾病，与世界其他国家比较，中国治疗肝癌和肺癌的病例数最多。6中国使用冷冻外科系统治疗肝癌文献复习2009年4月20日，我们使用中文关键词“肝癌and氩氦”检索了1999-2008年期间中国知识基础设施工程数据库(ChinaNational Knowledge Infrastructure，CNKI，CJFD)，并且，使用检索词”cryoablation and liver cancer”检索了收录在PubMed(MEDLINE)数据库中的中国作者文献。1999-2008年期间共有119篇中国冷冻治疗肝癌的文献，其中118篇文献大体分为14类别，分别是：(1)肝癌的氩氦刀冷冻治疗36篇；(2)超声引导氩氦刀冷冻消融治疗肝癌14篇l(3)CT引导氩氦刀冷冻消融治疗肝癌2篇；(4J肝动脉栓塞化疗联合氩氦刀冷冻消融治疗12篇。(5)原发性肝癌多种微创疗法的对比研究及临床应用9篇t(6J其他介入方法联合氩氦刀或手术联合氩氦刀治疗肝癌2篇，(7)肝癌氩氦刀冷冻术中静脉麻醉、监测、手术技巧3篇；(8)中西医结合氩氦刀消融治疗肝癌5篇；(9)经皮肝穿刺氩氦刀冷冻术治疗肝癌的副反应和并发症9篇，护理13篇。术后影像学方法评价疗效5篇；肝癌冷冻消融治疗合理选择与评价3篇，对于免疫学、肝功能等方面影响的实验室研究4篇；其他方面试验研究l篇。冷冻消融治疗后肿瘤患者l，2，3，4，5年生存率的统计也作了分析，分别是348-985，25-636，42-583，但是没有4，5年的生存率。冷冻消融为基础的联合治疗效果比单纯冷冻或TACE要好，联合冷冻治疗后l，2年的生存率分别是83和618-917。另外，与肝癌冷冻治疗有关的513篇文献收录在Medline中，其中40篇由中国作者写作。2008年Xu KC，Niu LZ，Hu YZ等总结了326例肝癌病人使用Endocare经皮氩氦冷冻消融治疗后1，2，3，4，5年的生存率，分别是78，62，41，3400，1112009年世界肿瘤介入学术大会汇编232006年，Chen SG，Zhang SM，Zhao HT等比较了73例以冷冻手术为基础的联合治疗(液氮，LCS-2000，英国生产)与239例以TACE为基础的联合治疗的生存率，l，3，5年生存率分别是644，384，274l和751，290，1002002年，Rui JA，Wang SBChela SG等报道了191例外科切除和70例冷冻外科(液氮)的治疗结果，l，3，5年生存率分别是758，456，304和632，37O，但是没有5年的冷冻外科结果。40篇文献中，16篇是由Zhou XD，Tang ZY，YuY等作者撰写，是关于液氮冷冻治疗肝癌病人的结果。2002年。他们报道了84例肝癌病人治疗后l，3，5年的生存率分别是987，839，64O总结：11)超声波或CT引导下的经皮冷冻消融治疗肝癌是一种安全有效的微创治疗技术。(2)联合TACE和冷冻消融治疗对于进展期原发性肝癌的疗效好于单一技术的疗效。(3)这种技术可以提高生存率和生活质量，对于失去手术切除治疗机会的肝癌患者，开创了一个新的治疗方式。(4)在冷冻消融治疗肝癌的微创介入治疗领域，中国对于世界作出了重大贡献。【关键词】肝癌。氩一氦液氮，冷冻消融，冷冻外科The latest progress of cryoablation therapy of primary liver cancer inChinaZhang Jiren Shj DegangCancer Center Zhujiang Hospital Southera Medical University Guangzhou ChinaIn t11is lecturethe development of cryoablation therapy of liver cancer in China is discussed，which include 6 aspects：1With the help of foreign friendsArgon-helium Cryoablation was introduced into ChinaArgonhelium cryoablation was the integration of more than 20 NASA patents of American hightech，which wasapproved bV FDA in 1998Dudng 19992002200 hospitals in the United States had installed this instrument，which hadreplaced liquid nitrogen and other cryosurgical equipmentThe first endocare cryocare surgical system has been used in zhujiang hospitalthe First Military Medical Universityin 1 999the C：hairman EKLehtinen and Vice，Chairman RHanka of International Biological Therapy Association cameto China for the Center ribbon-cuRingIn China，using endocare cryocarc surgical system，the first cryosurgery began inzhujiang hospital by Peter J LitrupZhang JR and Wang SM in 1 999Endocare cryocare surgical system was named勰Argonhelium Cryoablmion in ChinaIn 1999，by percutaneous cryoablation under CT guidance，the first patient withhepatocellular carcinoma was treated after transcather arterial chemoembolization(TACEl in Zhujiang hospitalOn behalf of collaboration group of Argonhelium cryosurgery in China，we will thank very much for foreign friendshelp and guidance for developing cryotherapy in ChinaThese professors were Peter J Litrrup，Suzy Chosy，DanielRukstalis，Andre，DPeterson，Gregory Groves，Daniel Rukstalis，Go Wakadayash，Winoruanabe and Dan silver,et a1Endocare cryocare surgical system had been used in the oncology center directed by the fellow members of Chineseacademician of medical science。they were、Vu mengchao，Hao xishan，Tang zhaoyou，Wu xianzhongFrom 1 9992007，Endocare Cryocare surgical system had been used in about 70 hospitals in China2The procedure of percutaneous cryoablation under imaging guidanceUnder the guidance of DSA，CT，MR，Laparoscopic，Ultrasound，cryoablation therapy is useful for treating solidtumor,such as lung cancer,liver cancer,glioma，soft tissue tumor,breast cancer,ovary cancer,bone tumors，pancreaticcancerprostate cancer,lenal cancel skin tumorsanalrectal cancel oral tumors。cervical intraepithelial neoplasia，et a1The targeted tissue of cryoablation was observed by imaging study on CT,MRPET and DSAThe clinical results had beenreported in China by several hospitalsTumor markers such as CEAkeP,PSA，CA 19-9 were detected before and aftercryoablation therapy in different kind of tumors3Basic study of targeted cryoablationThe effectiveness of cryosurgery on patients with entity tumor had been confirmed by(1)analysis on cancer anitaalmodels，(2)detection on tumor tissue of patient after cryosurgery，(3)study using immunology and molecular biologymethodsThe most often used cryoablation system was Endocare Cryoeare System produced in USArecently other cryosurgerysystem had been used in chinasuch as Galil Medical System(Israel)in more than 10 hospitalsIn addition，a kind of1122009年世界肿瘤介入学术大会汇编1iquid freezing cryoablation system is produced by Qinghua UniversitY,another kind of N2 freezing cryoablation systemis produced by Shanghai Jiaotong UniversitY,which might be found in medical market during 20082009The changes ofcancer cell line before and after cryotherapy were reported by several hospitals111e effects of cryotherapy on the normaltissues were also detected in animal model and patients with tumor,for example，the effects on artery and versus，biliary,pancreas and bronchial tube were also studiedThe changes of targeted tissue of tumor in vivo after cryoablation weredetected and followed up，and the reseeted tissue samples were also analysed in vitro111e impact factors of cryoablation therapy,such as cryoablation time，temperature，blood，argon and helium condition，needle diameters and targeted margin were also studied bv Chinese doctorsIts effectiveness had been confirmed in clinicaloncoiogy,and its standard procedure had been known by every doctorsMore over,the cryoimmunological programs hadbeen carrying on in the fields of DCs，TLs，NK，LAK，and cell factors in clinical oncology，over ten hospitals taking part inthis program4Clinical research of targeted CryoablationApart from surgical resection and interventional procedures，minimally invasive surgery has great significance in thetreatment of HCCCombination of chemotherapy and cryoablation in treating Nonsmall cell lung cancer was performedby Professor ZhaoCombining cryoablation with radiotherapy for treating 250 patients with Non-small cell lung carcinomawas reported by Song huazhi，their results demonstrated that the effects of combing Cryotherapy could prolong the survivalrate of l year and 2 yearsCombining TACE with cryoablation to treat 382 patients with HCC was also reported by Songhuazhi，with their effective rate TACE 328and TACE&Cryoablation 583，respectivelyIn the course of using cryoablation to treat cancer,the collaboration group of Argonhelium cryosurgery in Chinahad summarized the selection protocols of several kinds of treatment techniques for tumor,which included many aspects，such as indications，effect，toxicity，complications，impact to other therapies，relieve pain，the quality of life，reduce thepsychological burden、economic cost(social|family|units)The collaboration group of Argonhelium cryosurgery in China had called for manufacturers to address urgently forthe clinical problems about ablation technology，such as：range，threedimensional shape and clinical guidelines of ablationtarget；effects of physical and biological factors on the target；design the appropriate conformity of ablation target whenusing minimally invasive procedures；targeting position，guidance and navigation；real time monitoring and control of targetablation；evaluation standard of shortterm and longterm after target ablation；the treatment of subclinical and residuallesions；choice of comprehensive treatmentMore over,the collaboration group of Argonhelium cryosurgery in China hadalso stressed the position of ablation therapy in the modem model of tumor treatmentand t11ey had edited three books aboutcryotherapy in the fields of Cryocare targeted cryoablation therapy,Cryosurgery for Cancer and the freezing mechanism ofbiomedical engineeringSince 1999，5 international and 4 national conferences on targeted ablation and minimally invasivetherapy had been hold in China by our committee5Statistic number of cancer patients treated with Argonhelium Cryoablation in ChinaIn Novembet 2007the 1 4t11 Wbrid Congress of cryotherapy had a statistics of l 2 Chinese hospitals about Cllinas useof the United States CryocareTM Cryoablation system for treating tumor patients，with the number reached 1 l，000 cases，ofwhich more than 500 cases had completed in over 10 hospitals individually and some hospitals had completed删casesMore than 30 kinds of diseases were treated by cryotherapy，among which the numbers of liver cancer and lung cancer werethe most in China compared with any other countries in the world6Review of Iiteratures about Cryocare Surgical treatment of Iiver cancer in ChinaIIl 20th April 2009we use the Chinese key words“liver cancer and argon helium”to search articles in the l 9992008National Knowledge Infrastructure(CNKI，CJFD)，and more，use search words“cryoablation and fiver cancerto searchthe literatures of china included in PubMed(MEDLINE)A total of l 19 Chinese literatures of Cryocare treatment for liver cancer were found during the period of 19992008ofwhich ll 8 articles were divided into 14 categories roughlyThey were as followed(1)36 articles about hepatic cryoablationtherapy；(2)14 about ultrasoundguided cryoablation of liver cancer；(3)2 about CT guided cryoablation of liver cancer；(4)1 2 about combined TACE and Cryoablation；(5)9 about comparative study of a variety of minimally invasive therapyand clinical application in primary liver cancer；(6)2 about other interventional techniques combined with argonheliumcryoablation or surgical treatment combined with argonhelium cryoablation of liver cancer；(7)3 about intravenous1132009年世界肿瘤介入学术大会汇编anesthesia，monitoring and surgical techniques during intraoperative Cryocare frozen of liver cancer；18)5 articles abouttraditional Chinese and western medicine combined with Cryocare surgical ablation for the treatment of liver cancer；(9)9 articles about side effects and complications of cryoablation with percutaneous liver puncture in the treatment of livercancer；(10)l 3 of Nursing；(11)5 about postoperative imaging to evaluate the efficacy；(功3 about reasonable alternation andevaluation of cryoablation in Iiver cancer；4 articles of laboratory studies about immunology，liver function and otheraspects of the impact of cryoablation in liver cancer；04)l article about other aspects of the pilot studyThe statistics ofsurvival rate of 1iver cancer patients after cryoablation at l，2，3，4，5 years were also analyzed，which were 348985，25-63642583individuallybut without survival rate of 4 and 5 yearsEf佬ct of cryoablation based combined therapywas better than simple cryoablation or TACE，with the survival rate of combined cryoablation at l，2 years was 83and6 189 17individuallyIn addition，5 l 3 literatures about frozen treatment of liver cancer were included in Medline，in which 40 articles werewritten by Chinese authorsIn 2008，Xu KC，Niu LZ，Hu YZ，et al had summarize the survival rate of 326 cases of livercancer by percutaneous cryosurgery(Argon-helium，endocare cryocare system produced in USA)at l，2，3，4，5 year,whichwere 78，62，4 l，34，23，individuallyIn 2006，Chen SG，Zhang SM，Zhao HT，et a1had compared the survivalrate of liver cancer patients between 73 cases of cryosurgery-based combined therapy(1iquid nitrogen，LCS一2000 producedby Cryogenic Technology L1rD，UK)and 239 cases of 1ACEoriented combined therapy，with 1，3，5 years survival rate644，384，274；and 751，29O，lO0，individuallyIn 2002，Rui JA，Wang SB，Chen SG，et a1had reportedtheir results of 1 9 1 cases of surgical resection and 70