ACE联合分子靶向药物及免疫检查点抑制剂治疗肝癌的研究进展

【摘要】 目前,肝动脉栓塞化疗（transarterial chemoembolization,TACE）是中晚期肝细胞癌（HCC）的首选治疗方法。随着多靶点信号转导抑制剂及免疫治疗药物的发展,其在HCC治疗中有着越来越重要的地位。近年来TACE联合分子靶向药物或免疫治疗药物展示出较好的疗效,TACE联合索拉非尼、仑伐替尼、阿帕替尼等治疗中晚期HCC的中位无进展生存期（median progression-free survival,mPFS）以及总生存期（overall survival, OS）明显延长。TACE联合纳武利尤单抗、卡瑞利珠单抗等免疫治疗药物对中晚期HCC,也显示出良好的mPFS和OS率。现将TACE联合分子靶向药物及免疫药物治疗HCC的研究进展概述如下。     

TACE联合分子靶向药物治疗原发性肝癌的研究进展

传统放化疗对于不能手术的肝癌疗效有限,以经导管肝动脉化疗栓塞术（TACE）为主的综合治疗措施仍然是当前主要手段。然而反复的TACE可加重病人肝脏损伤,且栓塞治疗后局部缺血、缺氧,促进了血管内皮生长因子的活化,进而促进新生血管形成,导致肿瘤复发,降低疗效。近年来,分子靶向药物,尤其是多靶点索拉非尼的出现,开创了肿瘤治疗新领域,已成为当今肿瘤治疗的热点之一。TACE联合分子靶向药物具有独特优势,局部高浓度靶向药物导入及持续释放,不仅可提高抗肿瘤效果,还可弥补TACE术后复发等不足。两者具有良好的协同作用。现就TACE联合分子靶向药物治疗原发性肝癌的研究进展予以综述。     

TACE联合分子靶向药物治疗原发性肝癌的研究进展

传统放化疗对于不能手术的肝癌疗效有限,以经导管肝动脉化疗栓塞术(TACE)为主的综合治疗措施仍然是当前主要手段.然而反复的TACE可加重病人肝脏损伤,且栓塞治疗后局部缺血、缺氧,促进了血管内皮生长因子的活化,进而促进新生血管形成,导致肿瘤复发,降低疗效.近年来,分子靶向药物,尤其是多靶点索拉非尼的出现,开创了肿瘤治疗新领域,已成为当今肿瘤治疗的热点之一.TACE联合分子靶向药物具有独特优势,局部高浓度靶向药物导入及持续释放,不仅可提高抗肿瘤效果,还可弥补TACE术后复发等不足.两者具有良好的协同作用.现就TACE联合分子靶向药物治疗原发性肝癌的研究进展予以综述.     

肝动脉化疗栓塞联合抗血管生成药物治疗肝细胞癌

原发性肝细胞癌（HCC）是最常见的肝脏恶性肿瘤,多数患者确诊时已达中晚期,经导管肝动脉化疗栓塞（TACE）已成为其首选治疗方式。但TACE治疗有一定局限性,主要表现在栓塞不彻底,肿瘤组织缺血缺氧,导致残存肿瘤组织内缺氧诱导因子-1（HIF-1）水平升高,从而使血管内皮生长因子（VEGF）高表达,导致肝内肿瘤易复发和远处转移。抗血管生成药物主要作用是抑制VEGF的表达,与TACE联合可降低HCC的复发和转移。本文对近年应用于HCC的抗血管生成药物及联合TACE治疗进展进行综述。     

肿瘤血管生成的SPECT分子显像研究进展

肿瘤血管生成与肿瘤生长、转移有着密切的关系。肿瘤血管生成被各种蛋白分子调控,其中包括血管内皮生长因子、αvβ3整合素、细胞外基质蛋白、前列腺特异性膜抗原等。它们已成为肿瘤血管生成分子影像及靶向治疗研究领域的重要分子靶点。研究并利用这些蛋白分子准确无创地评估肿瘤新生血管及肿瘤抗血管生成治疗效果的成像方法,已成为现代医学影像学的一个重要课题。     

TACE联合分子靶向药索拉菲尼治疗晚期肝癌远期疗效观察

目的 评价经肝动脉灌注化疗栓塞术(TACE)联合分子靶向药物甲磺酸索拉菲尼治疗晚期肝细胞肝癌(HCC)的临床疗效和不良反应.方法 2007年6月至2009年5月,江苏省肿瘤医院介入科收治的30例晚期HCC患者,采用经TACE或单纯动脉灌注化疗,术中用药为氟脲苷1.0 g,羟基喜树碱20 mg,吡柔比星30 mg,碘油栓...     

VEGFR小分子抑制剂研究的新进展

血管生成是肿瘤生长、增殖和迁移必不可少的过程.血管内皮生长因子受体(VEGFR)作为影响血管生成的关键信号因子,已成为抗肿瘤药物研发的重要靶点.已证实VEGFR是肾细胞癌、胃肠道间质瘤、肝细胞癌、白血病等多种类型肿瘤的治疗靶点.该文综述了临床应用的14个VEGFR抑制剂及处于临床试验阶段VEGFR小分子抑制剂的研究进展...     

动脉内恩度联合化疗栓塞术治疗原发性肝癌前后CT灌注成像的随机对照研究

目的 随机对照研究动脉内重组人血管内皮抑制素(恩度TM EndostarTM)联合化疗栓塞(TACE)治疗原发性肝癌(HCC)前后CT灌注参数的变化.资料与方法 40例临床诊断为HCC的患者,随机分成两组,各加例,分别使用动脉内恩度加TACE术及单纯TACE术,所有病例于TACE术前、术后1个月行CT灌注成像(CTPI)扫描,测量肿瘤组织治疗前后血流量(BF)、血容量(BV)、血管表面渗透面积(PS)、肝动脉灌注值(ALP)、门静脉灌注值(PVP)及肝脏灌注指数(HPI).结果 动脉内恩度加TACE术组HCC患者术后1个月CTPI扫描肿瘤组织BF、ALP及HPI水平较术前降低,PVP水平较术前升高,BV、PS水平与术前相比无显著性差异;单纯TACE术组HCC患者术后1个月ALP水平较术前降低,PVP水平较术前升高,BV、BF、PS及HPI水平与术前相比无显著性差异.结论 通过比较两组HCC患者TACE前后CT灌注参数的变化,说明恩度对肿瘤血管生成有一定的抑制作用.     

免疫检查点抑制剂联合TACE在肝癌治疗中的研究进展北大核心CSCD

近年来,免疫检查点抑制剂(ICI)是肝细胞癌(HCC)系统治疗的研究热点,ICI是指针对免疫系统中抑制性的信号通路和受体的阻断剂。经动脉导管化疗栓塞术(TACE)和ICI的疗效及适应证有一定差异,部分临床试验发现TACE联合ICI有协同抗肿瘤作用,能提高肿瘤应答率。这些临床试验主要是评估联合治疗的长期生存率和安全性。本文就ICI联合TACE在治疗HCC中的协同抗肿瘤机制和疗效进行简要综述。     

肝动脉化疗栓塞联合血管内皮抑素治疗肝癌的临床应用

目的研究肝动脉化疗栓塞联合血管内皮抑素治疗肝癌的临床疗效。方法治疗组20例为TACE联合重组人内皮抑素经动脉灌注,对照组20例为单纯TACE,所有患者术后1年内每2月复查彩超检查,观察肿瘤控制情况、新生血管抑制情况,并观察1年内生存率。结果治疗组1年生存率高于对照组(P=0.035),治疗组肿瘤新生血管抑制率明显高于对照组(P=0.025),治疗组疾病控制率(DCR)显著高于对照组(P=0.038)。结论内皮抑素联合TACE治疗肝癌,患者1年生存率显著提高,肿瘤新生血管、转移抑制明显,值得临床推广。     

肝癌分子靶向药物及免疫抑制剂治疗的研究现状及进展

肝癌是全球癌症发病率第6位，死亡率第3位的恶性肿瘤。肝癌发病隐匿且发展迅速，多数患者发现时病情就已经进展到中晚期，丧失了手术根治的机会。索拉非尼作为抗血管生成的分子靶向药物开启了肝癌分子靶向治疗的先河，在随后的近十年内，针对肝癌的靶向药物不断涌现，瑞戈非尼、乐伐替尼、卡博替尼、雷莫芦单抗以及一些免疫抑制剂在Ⅲ期临床试验方面取得了不错的成绩。本文就新出现的抗血管分子靶向药物及免疫抑制剂治疗肝癌的现状、挑战以及未来的发展方向进行综述。     

TACE联合中药治疗不可切除肝细胞癌的研究进展

肝细胞癌（HCC）是我国常见的恶性肿瘤之一，而对于中晚期的肝癌患者，大多数已丧失外科手术切除的机会，此时经皮肝动脉化疗栓塞术（TACE）是目前为止的首选治疗方案。虽然它有着较好的临床疗效，但其不良反应也是临床医生所必须面对的问题。传统中药由于药性温和，不良反应较少，可以减少化疗药物的用量，提高机体的免疫力，故采用TACE联合中药治疗原发性肝癌也逐渐被临床医生所推广。文章旨在综述康莱特、榄香烯、槐耳颗粒及肝复乐等中药与TACE联合治疗HCC的应用情况和优势。     

Hepatocellular carcinoma: treatment with transcatheter arterial chemoembolization

This article presents a review of the literature regarding the use of transcatheter arterial chemoembolization (TACE) in the treatment of hepatocellular carcinoma (HCC). There have been two different approaches to the treatment: (a) percutaneous tumor ablation methods which can be divided into injectable and thermal methods; percutaneous ethanol injection (PEI) is the most widely used method, and (b) TACE. PEI is the treatment of choice for single HCCs smaller or equal to 3 cm in size. For patients with large HCCs combined TACE and PEI is probably the most effective nonsurgical treatment. In the presence of multiple HCC nodules, TACE remains the treatment of choice.     

比较肝动脉化疗栓塞联合经皮乙醇注射与联合冷循环微波刀治疗原发性肝癌的疗效

目的比较肝动脉化疗栓塞（TACE）联合经皮乙醇注射（PEI）与TACE联合冷循环微波刀术（PMCT）治疗原发性肝癌的效果。 方法150例患者接受TACE联合PEI,160例患者接受TACE联合PMCT治疗。术后4周复查动态增强CT,观察疗效。 结果TACE+PEI或TACE+PMCT后1个月,肿瘤一次消融率分别为70.00%和87.67%,TACE+PMCT组的疗效要优于TACE+PEI组（P<0.05）。 结论TACE+PMCT是原发性肝癌的有效治疗方法,是单纯TACE疗效不佳者的理想选择。     

Review on transarterial chemoembolization in hepatocellular carcinoma: palliative, combined, neoadjuvant, bridging, and symptomatic indications

The current review provides an overview on the palliative, combined, neoadjuvant, bridging, and symptomatic indications of transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC). It is based on an analysis of the current literature and the experience of the authors on the topic. Chemoembolization combines the infusion of chemotherapeutic drugs with particle embolization. Tumor ischemia raises the drug concentration compared to infusion alone, extends the retention of the chemotherapeutic agent and reduces systemic toxicity. Palliatively, TACE is performed to control symptoms and prolong survival in HCC patients; in some indications TACE allows a local tumor control of 18-63%. For combined indications, excellent results were achieved by combined therapies, such as percutaneous ethanol injection (PEI)/TACE, radiofrequency ablation (RF)/TACE, and laser-induced thermotherapy (LITT)/TACE. As a neoadjuvant therapy prior to liver resection TACE showed 70% tumor control. Though debatable, TACE still plays a role as a bridging tool before liver transplantation. Symptomatic indication of TACE in ruptured HCC showed 83-100% control of bleeding but survival was poor. Thus, TACE represents an important therapeutic tool against HCC in general in addition to its special role in cases of unresectable HCC.     

肝动脉化疗栓塞联合CT引导下射频消融术治疗肝癌的疗效分析

目的 评价肝动脉化疗栓塞(TACE)联合CT引导下射频消融术(RFA)治疗肝癌的疗效.方法 HCC患者200例先行TACE术,然后在CT引导下行RFA术.200例患者共行TACE术495例次.肿瘤病灶共计378个,直径为O.5-16 cm,共行RFA术362人次,663个位点.结果 术前、术后12个月AFP分别为(2 156.79±574.61)ng/ml、(269.53±146.65)ng/ml,两者差异有统计学意义(t=16.11,P<0.01).术前、术后3、6和12个月的肿瘤体积分别是(72.64±24.74)cm3、(46.78±18.95)cm3、(28.27±11.70)cm3和(10.82±8.31)cm3,差异有统计学意义(F=10.77,P<0.01).肿瘤完全坏死率为87.8%.结论 肝TACE联合CT引导下RFA治疗肝癌是一种有效的微创治疗方法.     

肝动脉化疗栓塞联合射频消融或放射性粒子组织间放疗对原发性肝癌的疗效比较研究

目的 评价比较肝动脉化疗栓塞(TACE)联合射频消融(RFA),以及TACE联合放射性粒子组织间放疗治疗原发性肝癌的效果.方法 50例患者接受TACE联合RFA,34例患者接受TACE联合125I组织问放疗.术后4周复查动态增强CT或MR,对病灶碘油聚集不良者,再次行TACE,术后定期复查,观察疗效.结果 TACE联合RFA或125I放疗后1个月.肿瘤局部控制率分别为98.0%和97.1%,两组间差异无统计学意义.结论 TACE联合RFA和125I植入放疗是肝细胞性肝癌的有效的治疗方法,是单纯TACE疗效不佳者的理想选择.     

Review on transarterial chemoembolization in hepatocellular carcinoma: Palliative,combined, neoadjuvant,bridging, and symptomatic indications

The current review provides an overview on the palliative, combined, neoadjuvant, bridging, and symptomatic indications of transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC). It is based on an analysis of the current literature and the experience of the authors on the topic. Chemoembolization combines the infusion of chemotherapeutic drugs with particle embolization. Tumor ischemia raises the drug concentration compared to infusion alone, extends the retention of the chemotherapeutic agent and reduces systemic toxicity. Palliatively, TACE is performed to control symptoms and prolong survival in HCC patients; in some indications TACE allows a local tumor control of 18–63%. For combined indications, excellent results were achieved by combined therapies, such as percutaneous ethanol injection (PEI)/TACE, radiofrequency ablation (RF)/TACE, and laser-induced thermotherapy (LITT)/TACE. As a neoadjuvant therapy prior to liver resection TACE showed 70% tumor control. Though debatable, TACE still plays a role as a bridging tool before liver transplantation. Symptomatic indication of TACE in ruptured HCC showed 83–100% control of bleeding but survival was poor. Thus, TACE represents an important therapeutic tool against HCC in general in addition to its special role in cases of unresectable HCC.     

不同治疗方案对晚期肝细胞性肝癌预后的影响及因素分析

目的：研究单纯和联合治疗方案对晚期肝细胞肝癌（HCC）预后的影响,分析影响预后的主要因素。 方法：回顾性分析2014年我院收治的133例晚期HCC患者,统计24项预后相关数据,采用Cox单因素和多因素回归模型分析预后影响因素。统计患者接受的所有治疗方式,并分为3种治疗方案：（1）保守治疗58例;（2）单纯肝动脉化疗栓塞术（TACE）治疗58例;（3）联合治疗17例：TACE联合索拉菲尼或者TACE联合立体定向放疗（SBRT）。Kaplan-Meier法绘制生存曲线,并使用Log-rank检验比较患者生存期差异。 结果：133例患者总体中位生存期为7.6个月,其中6个月、1年、2年的生存率分别为57%、30%、12%。多因素分析证明Child-Pugh分级、门静脉癌栓类型、肝外转移类型以及甲胎蛋白水平为影响预后的独立因素。治疗方案上,TACE联合索拉菲尼与TACE联合SBRT之间无明显差异,但均明显优于单纯TACE治疗,且单纯TACE治疗明显优于保守治疗。 结论：Child-Pugh分级、门静脉癌栓类型、肝外转移类型和甲胎蛋白水平是影响晚期HCC预后的独立因素。TACE联合索拉菲尼或TACE联合SBRT的预后均优于单纯TACE治疗,单纯TACE治疗优于保守治疗。     

The Current Practice of Transarterial Chemoembolization for the Treatment of Hepatocellular Carcinoma

Despite remarkable advancement in the surveillance and treatment of hepatocellular carcinoma (HCC) and the availability of novel curative options, a great proportion of HCC patients are still not eligible for curative treatment due to an advanced tumor stage or poor hepatic functional reserve. Therefore, there is a continuing need for effective palliative treatments. Although practiced widely, it has only recently been demonstrated that the use of transarterial chemoembolization (TACE) provides a survival benefit based on randomized controlled studies. Hence, TACE has become standard treatment in selected patients. TACE combines the effect of targeted chemotherapy with the effect of ischemic necrosis induced by arterial embolization. Most of the TACE procedures have been based on iodized oil utilizing the microembolic and drug-carrying characteristic of iodized oil. Recently, there have been efforts to improve the delivery of chemotherapeutic agents to a tumor. In this review, the basic principles, technical issues and complications of TACE are reviewed and recent advancement in TACE technique and clinical applicability are briefed.