肝癌介入文献集.pdf

目目 录录 Roles Played by chemolipiodolization and embolization in chemoembolization for Hepatocellular carcinoma: Single-Blind, randomized trial 1 经皮肝动脉栓塞化疗联合洛铂热灌注化疗治疗不能手术切除的肝细胞癌的近期 疗效观察 10 TACE 治疗大肝癌合并门脉癌栓：一项前瞻、非随机对照研究 13 洛铂与碘油栓塞化疗用于肝脏原位移植术后的复发性肝癌且不能通过手术切除 的患者 20 肝动脉栓塞化疗不同化疗方案治疗不可切除肝癌的肝动脉栓塞化疗不同化疗方 案治疗不可切除肝癌的前瞻性随机对照研究 27 洛铂对肝癌的细胞周期抑制作用研究 31 肝癌介入文献集JNCI | Articles 59jnci.oxfordjournals.orgArticleroles Played by chemolipiodolization and embolization in chemoembolization for Hepatocellular carcinoma: Single-Blind, randomized trialMing Shi, Li-Gong Lu, Wan-Qiang Fang, Rong-Ping Guo, Min-Shan Chen, Yong Li, Jun Luo, Li Xu, Ru-Hai Zou, Xiao-Jun Lin, Ya-Qi ZhangManuscript received June 25, 2012; revised September 17 , 2012; accepted September 17 , 2012.Correspondence to: Ming Shi, MD, Department of Hepatobiliary Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, 510060, P .R. China (e-mail: ). Background The aim of our study was to compare the efficacy and safety of: 1)transarterial chemolipiodolization with gela-tin sponge embolization vs chemolipiodolization without embolization, and 2)chemolipiodolization with triple chemotherapeutic agents vs epirubicin alone. Methods A single-blind, three parallel arm, randomized trial was conducted at three clinical centers with patients with biopsy-confirmed unresectable hepatocellular carcinoma. Arm 1 received triple-drug chemolipiodolization and sponge embolization, whereas Arm 2 received triple-drug chemolipiodolization only. Patients in arm 3 were treated with single-drug chemolipiodolization and sponge embolization. We compared overall survival and time to progression. Eventtime distributions were estimated by the KaplanMeier method. All statistical tests were two-sided. Results From July 2007 to November 2009, 365 patients (Arm 1: n=122; Arm 2: n=121; Arm 3: n=122) were recruited. The median tumor size was 10.9 cm (range=722 cm), and 34.5% had macrovascular invasion. The median sur-vivals and time to progression in Arm 1, Arm 2, and Arm 3 were 10.5 and 3.6months, 10.1 and 3.1months, and 5.9 and 3.1months, respectively. Survival was statistically significantly better in Arm 1 than in Arm 3 (P 60 109 platelets/L; hemoglobin: 8.5 g/L; and prothrom-bin time: 10 cm). For two centers, the random block size for each stratum was 9 and 18. For the third center, where the subject recruitment rate was expected to be lower, the random block size for each stratum was 6 and 12. The three treatment groups were as follows:1. Arm 1 received triple-drug chemolipiodolization with embo-lization. Lobaplatin (50 mg), epirubicin (50 mg), and mitomy-cin C (6 mg) were mixed in 9 mL of water-soluble contrast medium and 1 mL of sterile water for injection. The mixture was thoroughly mixed with 10 mL of lipiodol. After injec-tion of the emulsion, 20 mL of pure lipiodol were injected. The injection was stopped either at the point of near stasis within the main artery feeding the tumor or after the entire amount of the above agent was administered. The actual vol-ume administered was recorded. After that, embolization was performed with injection of gelatin-sponge particles 500 to 1000? m in diameter through the catheter to reach stasis in the tumor-feeding artery.2. Arm 2 received triple-drug chemolipiodolization without embolization. Chemolipiodolization was performed with the same combined regimen without gelatin-sponge embolization.3. Arm 3 received single-drug chemolipiodolization with embo-lization. Treatment was the same as for Arm 1, except that only a single-drug, epirubicin (50 mg), was used.Study EndpointThe primary endpoint was the comparison of overall survival among the different treatment arms. After inclusion of the last patient in the study, a follow-up period of 12months was scheduled. Follow-up ended on December 1, 2010. The secondary outcome was the time to radiological progression (TTP), which was defined as the time from random assignment to disease progression.Statistical AnalysisFor comparisons of baseline variables, the Students t test for continuous variables and the ?2 test for categorical variables were used. Treatment response and survival time were determined on an intent-to-treat basis. The survival curves and univariable analysis were calculated by the KaplanMeier method and compared using a log-rank test. Any factors that were statistically significant at P less than .10 in the univariate analysis were candidates for entry into a multivariable Cox proportional hazards model, the results of which are presented for the last step of the reverse selection of random variables. The proportional hazard assumption was checked by graphical inspection of the linearity of the hazards over time and loglog plots and by plotting Schoenfeld residuals over time. P values less than .05 were considered statistically significant. All statistical tests were two-sided. We analyzed the data for differences by sex but did not analyze ethnicity data. All statistical processing was performed by the Statistical Package for Social Science version 13.0 (SPSS Inc., Chicago, IL).肝癌介入文献集第 2 页，共 39 页1. 组1接受三联化疗药物碘化油乳剂联合动脉栓塞。洛铂（50 m g ）、表柔比星（50 m g ）、丝裂霉素（6 m g ）混入9m l 水溶性造影剂和1m l 无菌注射用水中，将混合物与10 m l 的碘化油充分混匀。注射乳剂后，再注射2 0 m l 纯碘化油。组2 接受三联化疗药物碘化油乳剂，不联合动脉栓塞组3接受单药化疗药物碘化油乳剂联合动脉栓塞。治疗方法同组1相同， 但只使用一种化疗药物，表柔比星（50 m g ）。JNCI | Articles 61jnci.oxfordjournals.orgresultsPatient CharacteristicsFrom July 2007 to November 2009, 381 patients were registered for the study; 16 (4.2%) patients were excluded because the TACE procedure could not be accomplished (Figure1). In total, 122, 121, and 122 patients were allocated to Arm 1, Arm 2, and Arm 3, respec-tively. The data from these patients were included in all subsequent analyses. The median tumor size was 10.9 cm (range=722 cm). Figure1. CONSORT flow diagram. TACE=transarterial chemoembolization.肝癌介入文献集第 3 页，共 39 页Vol. 105, Issue 1 | January 2, 201262 Articles | JNCITable1. Baseline characteristics and univariable analysis for all recruited patients*Baseline characteristics analysisUnivariable analysisCharacteristicArm 1, n=122Arm 2, n=121Arm 3, n=122PNo.Median survival time, monthsPSex.31.07 Men1151131093378.3 Women78132812.4Age, y.54.001 507768722177 .2 5045535014811.9Neutrophil:lymphocyte ratio.94.001 372727021410.9 35049521515.9Platelet count, 109/L.08.83 1008716319.1 1001141141063348.3Prothrombin time, s.50.04 141091061003158.9 14121521487 .2Hepatitis B surface antigen.02.06 Positive1141021143308.1 Negative81983512.2HBV DNA, copy.90.15 10004546431349.3 10007775792318.1Alanine aminotransferase, U/L.39.54 404049411308.4 408272812358.3Aspartate aminotransferase, U/L.16.007 452434238112.4 459887992847 .6Alkaline phosphatase, U/L.17.05 11049574314910.4 1107364792167 .6Glutamyl transpeptidase, U/L.331008791972757 .3Serum albumin, g/L.19.001 37272335857 .0 379598872809.5Total bilirubin, mol/L.81.001 209793932839.7 20252829825.6Alpha-fetoprotein, ng/mL.842007976812366.8Indocyanine green retention rate in 15 min, %.57.73 101081041003128.4 10141722537 .2Liver cirrhosis.90.58 No cirrhosis5258531638.4 Child A7063692028.3Tumor size, cm.27.007 1046585315710.9 107663692087 .4Tumor number.27.78 Single4951531538.7 Multiple7370692128.3Portal vein tumor thrombus.7626150501618.2BCLC stage.79.001 Stage B (intermediate)82807723911.9 Stage C (advanced)4041451265.4* Arm 1?=?three-drug chemolipiodolization with embolization; Arm 2?=?three-drug chemolipiodolization without embolization; Arm 3?=?single-drug chemolipiodolization with embolization. BCLC?=?Barcelona Clinic Liver Cancer; CLIP?=?Cancer of the Liver Italian Program; HBV?=?hepatitis B virus. P value was calculated by a two-sided 2 test. P value was calculated with two-sided log-rank test.Table 1. (Continued)Table2. Treatment numbers administered for each arm*Types of TreatmentArm 1, n=122Arm 2, n=121Arm 3, n=122Study TACE sessions211201180Subsequent treatments Hepatic resection15109 Radiofrequency ablation32216 TACE331015 Sorafenib769 Antiviral therapy121510* Arm 1?=?three-drug chemolipiodolization with embolization; Arm 2?=?three-drug chemolipiodolization without embolization; Arm 3?=?single-drug chemolipiodolization with embolization; TACE?=?transarterial chemoembolization.肝癌介入文献集第 5 页，共 39 页本研究中患者的肿瘤缓解率见表4.客观缓解率在组1、组2、组3分别为45.9%29.7%, 和18.9%。Vol. 105, Issue 1 | January 2, 201264 Articles | JNCIpatients in Arm 1, 94 patients in Arm 2, and 104 patients in Arm 3.For all 365 recruited patients, their overall survival at 6months, 1year, and 2years was 63.2%, 38.6%, and 22.7 %, respectively. The median survivals in Arm 1, Arm 2, and Arm 3 were 10.5, 10.1, and 3.1months, respectively. Survival was statistically significantly better in Arm 1 than in Arm 3 (P .001), whereas there was no sta-tistically significant difference between the two arms treated with triple-drug chemolipiodolization with or without embolization (Arm 1 vs Arm 2: P =.20) (Table4; Figure2).The analysis stratified according to the BCLC stage (stage B vs stage C) is shown in Figure3. In both stage B and stage C HCC patients, Arm 1 had statistically significantly improved survival out-comes when compared with Arm 3 (P =.02, P =.003, respectively), and there was no statistically significant difference between Arm 1 and Arm 2 (P =.93, P =.13, respectively) (Figure3).Univariable and Multivariable Analysis of Predictors of SurvivalThe results of univariable survival analysis are listed in Table1. In multivariable analysis, independent risk factors of survival were treatment allocation Arm 1 vs Arm 3 (hazard ratio HR =1.80, 95% CI=1.35 to 2.39; P .001), treatment allocation Arm 1 vs Arm 2 (HR=1.21, 95% CI=0.91 to 1.61; P =.20), age (HR=0.98, 95% CI=0.97 to 1.00; P =.003), neutrophil:lymphocyte ratio (HR=1.12, 95% CI=1.06 to 1.19; P .001), serum albumin (HR=0.95, 95% CI=0.93 to 0.98; P0.001), total bilirubin (HR=1.02, 95% Table4. Summary of patients outcomes*OutcomeArm 1, n=122Arm 2, n=121Arm 3, n=122PArm1 vs Arm 2Arm1 vs Arm 3Overall survival, months.20.001 Median10.510.15.9 95% CI8.3 to 12.86.0 to 14.04.2 to 7 .6Time to radiological progression, months.89.071 Median3.63.13.1 95% CI2.4 to 4.81.6 to 4.52.0 to 4.2Tumor response evaluation, % Objective response45.929.718.9.009.001 Complete response00.8 Partial response45.928.918.9 Stable disease25.434.730.3 Progressive disease23.829.743.4 Not evaluated4.95.97 .4* Arm 1?=?three-drug chemolipiodolization with embolization; Arm 2?=?three-drug chemolipiodolization without embolization; Arm 3?=?single-drug chemolipiodolization with embolization; CI?=?confidence interval Two sided P-value was calculated after covariable adjustment by multivariable Cox proportional-hazards analysis. P value was calculated by a two-sided 2 test. There were 22 patients who could not be evaluated for treatment response because of death, poor performance status, or patients refusal of computed tomography scan at 6 weeks.Table3. Number of complications that occurred in studied transarterial chemoembolization sessions*Incidence of complicationsArm 1, n=211Arm 2, n=201Arm 3, n=180PAny gradeGrade 35Any gradeGrade 35Any gradeGrade 35Arm 1 vs Arm 2 (any grade)Arm 1 vs Arm 3 (any grade)Postembolization syndrome Fever151313411420.28.10 Pain1020890920.41.59 Vomiting50124011373.35.46Blood Platelets13101331811.90.16 Hemoglobin774332.40.30 Leukocytes423010.75.24Liver function change Ascites/pleura effusion8080110.92.29 Edema: limb302060.69.21 Liver dysfunction321410340.16.33Renal failure220000.17.19Bleeding211011.59.66* Arm 1?=?three-drug chemolipiodolization with embolization; Arm 2?=?three-drug chemolipiodolization without embolization; Arm 3?=?single-drug chemolipiodolization with embolization. P value was calculated by a two-sided 2 test. Postembolization syndrome or blood change or liver function change might include more than one complication item.肝癌介入文献集第 6 页，共 39 页组1、组2、组3的中位生存时间分别为10.5,10.1,和3.1个月JNCI | Articles 65jnci.oxfordjournals.orgCI=1.01 to 1.03; P .001), alpha-fetoprotein (HR=1.46, 95% CI=1.13 to 1.90; P =.004), and BCLC stage (HR=2.07, 95% CI=1.62 to 2.64; P 3 个月。每例接受治疗 2次。所有病例均经病史、 症状、 实验室检查和B超、CT等影像学检查均确诊为肝细胞癌。Early-stage therapeutic effects of thermochemotherapy andembolization via hepatic artery intervention in the treatment ofunresectable primary liver cancerPeng ZHANG, Xiaobing LI, Huhu REN, Feipeng WEI, Xiaoyu LIU, Weidong GONGCorrespondence to: Weidong GONG; E-mail: Department of Interventional Radiology, Tang Du Hospital, Fourth Military Medical University, Xian 710032, ChinaAbstractObjective:This study aims to explore the early-stage therapeutic effects of lobaplatin-based thermochemotherapy andembolization via hepatic artery intervention in the treatment of unresectable primary liver cancer.Methods:Thermochemotherapy andembolization were used to treat 20 unresectable primary liver cancer patients. Epirubicin, mitomycin, and lobaplatin were used for ther-mochemotherapy. The process was repeated once after 40 d to 50 d.After the two treatment periods, the early effects and side effects wereobserved.Results:Among the 20 cases, 4 (20.0%) received excellent efficacy, 7 (35.0%) received good effect, 7 (35.0%) demonstratedstabilization, and 2 showed advancement, with a total effective rate of 55.0%. The content of alpha fetoprotein dropped by over 50% in 8cases, among which 2 returned to normal.Conclusion:The use of thermochemotherapy and embolization via hepatic artery interventionis an effective and safe treatment for primary liver cancer. However, the long-term effects of this treatment need further observation.Keywords:primary hepatocellular carcinoma, transcatheter, thermochemotherapy, embolization经皮肝动脉栓塞化疗联合洛铂热灌注化疗治疗不能手术切除的肝细胞癌的近期疗效观察张鹏李晓冰任虎虎卫飞鹏刘晓宇宫卫东摘要目的：探讨经皮肝动脉栓塞化疗联合洛铂热灌注化疗在治疗肝细胞癌中的近期疗效。方法：对20例不能手术切除的肝细胞癌患者进行肝动脉热灌注化疗栓塞术， 先采用洛铂联合盐酸表柔比星、 丝裂霉素行热灌注化疗， 然后行常规肝动脉栓塞化疗， 间隔4050天再次治疗， 2次治疗后评价近期治疗效果及不良反应。结果：20例患者显效4例 （20.0%） ， 有效7例 （35.0%） ， 稳定7例 （35.0%） ， 进展2例 （10.0%） 。总有效率为55.0%。AFP下降50%者8例， 其中2例恢复正常。结论：肝动脉热灌注洛铂为主的联合化疗方案+栓塞术治疗肝细胞癌安全有效， 其远期疗效有待进一步观察。关键词原发性肝癌介入热化疗栓塞doi:10.3969/j.issn.1000-8179.2013.05.010作者单位： 第四军医大学唐都医院介入放射科（西安市710038）通信作者： 宫卫东284肝癌介入文献集第 10 页，共 39 页中国肿瘤临床 2013年第40卷第5期Chin J Clin Oncol 2013, Vol. 40, No. 5 1.2治疗方法采用Seldinger 技术进行股动脉插管， 导管为5F的RH导管， 必要时使用微导管。常规行腹腔动脉、肝总动脉、 肠系膜上动脉造影， 发现肿瘤染色后在肿瘤的主要供血动脉内灌注药物。将表柔比星30 mg、丝裂霉素8mg用生理盐水稀释后， 用介入热灌注治疗机 （珠海和佳HGC-3000） 进行灌注， 设置加热温度为5560， 灌注速度为36 mL/min。热灌注后将洛铂50 mg与1020 mL的超液态碘化油进行乳化， 热灌注结束后行乳化的碘化油进行栓塞。治疗中严密监测生命体征， 予以止吐等对症处理。1.3疗效评价根据首次治疗前及第二次治疗后46周增强CT检查， 参照改良的RECIST3进行评价， 近期疗效判断分为四级： 所有的目标病灶动脉增强显影均消失为完全缓解； 目标病灶 （动脉增强显影） 的直径总和缩小30%为部分缓解； 缩小未达部分缓解或增加未达疾病进展为疾病稳定； 目标病灶 （动脉增强显影）的直径总和增加20%或出现新病灶为疾病进展。以完全缓解和部分缓解为总有效率。1.4统计学分析应用SPSS 11.0统计学软件， 采用t检验比较治疗前后甲胎蛋白 （AFP） 的值， P50者8例， 其中2例恢复正常。2.3术后反应和并发症20例患者术后均出现不同程度的发热、 恶心、 呕吐、 腹痛等栓塞后综合征， 上述症状经对症处理后可逐渐缓解， 未见胆囊炎、 溃疡性出血和门脉高压性出血， 无治疗相关性死亡。3讨论随着肝动脉插管技术的发展和成熟以及经验的积累， 中晚期肝癌的治疗效果明显提高。TACE是治疗中晚期肝癌患者最有效的方法之一 4-5 。但TACE的总体疗效仍不甚满意， 根据日本学者的统计， 肝癌手术切除的5年生存率为40.8%， 而TACE则为8.0%6。另有文献报道原发性肝癌经TACE治疗的1、 3、 5年生存率分别在50%、 20%和6%7。任何一种单一治疗模式， 都难以治愈肝癌， 提高肝癌总体疗效依赖于综合治疗已成共