2023肝癌合并门静脉癌栓局部治疗进展.docx

2023肝癌合并门静脉癌栓局部治疗进展摘要肝细胞癌合并门静脉癌栓在临床上仍是一个棘手问题。局部治疗新技术、 新理念不断出现，多学科综合治疗理念不断强化，局部治疗联合系统治疗、 免疫治疗和局部治疗之间相互应用使病人生存率获得提高，病人预后获得 改善。未来更应该重视针对门静脉癌栓的局部治疗、系统治疗、免疫治疗 联合应用的新方向以及门静脉癌栓诊断创新技术研究。门静脉癌栓(portal vein tumor thrombus , PVTT )是肝细胞癌 (hepatocellular carcino , HCC )侵犯血管的主要形式。HCC病人合并 PVTT的发病率为44.0%62.2% ,合并PVTT未行任何干预的病人中位 生存期仅为2.7个月，明显低于未合并PVTT病人1 -3 随着近年来局 部治疗、免疫治疗以及联合治疗方案的出现，HCC合并PVTT病人的总生 存率有显著提高。本文重点针对联合局部治疗、免疫治疗以及系统治疗方 案治疗HCC合并PVTT病人的最新国内外进展进行综述。1PVTT分型及治疗策略目前，临床上常见的PVTT分型有3种，分别是日本肝癌研究小组4 1 程氏分型5 ,徐氏分型6 1日本肝癌研究小组的Vp分型是最早提出 以及国外最常用的PVTT分型。在我国，程氏分型应用更加广泛，其与Vp 分型相比增加了IV型肠系膜上静脉癌栓。徐氏分型基于肝切除术在HCC 好的抗肿瘤活性且毒性反应可控52 J, Cai等53 研究发现TACE联 合乐伐替尼联合PD-1抑制剂较TACE联合乐伐替尼治疗相比，可有效延 长晚期HCC病人的总生存期(16.9个月个月)以及提高客观缓 解率(56.1 %vs.32.5% );然而在亚组分析结果中，对于合并PVTT HI型 的HCC病人，并没有获得更好的生存益处。未来仍需大量前瞻性及多中心研究证明其安全性及有效性。相信 通过进一步探究其可能会成为治疗针对HCC合并PVTT病人的新途径。5 展望目前HCC合并PVTT仍是一个棘手的问题，当前的治疗方案不能有效提 高病人生存率，相关指南推荐的治疗方案差异也较大。近年来越来越多的 研究结果发现，局部治疗可以提高病人生存率，改善病人预后。但上述新 兴治疗方案的临床研究较少，仍需进一步验证其可行性、有效性以及在 PVTT各分型病人中的临床收益。未来应更加重视多学科联合治疗在临床 中的实践，应继续强化系统治疗、免疫治疗及局部治疗或局部治疗之间联 合应用的多学科综合治疗理念，进一步探索局部治疗、系统治疗及免疫治 疗的联合应用新方向。未来更应关注临床诊疗中PVTT的诊断以及分型金 标准，减少CT及MRI可能造成的漏诊及误诊；可以利用人工智能，根据 其影像特征建立预测模型以达到精准诊断及分型的目的，从而制定适合不 同分型PVTT病人的最佳治疗方案。参考文献1 Takizawa D, Kakizaki S, Sohara N, et al. 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Front Immunol, 2021,12:792781.25 Giorgio A, Di Sarno A, de Stefano G, et al. Hepatocellular carcinoma with cirrhosis: are patients with neoplastic main portal vein invasion eligible for percutaneous radiofrequency ablation of both the nodule and the portal venous tumor thrombus? J . Am J Roentgenol, 2009,193(4):948-954.26 Zhou Q, An Y, Liu T, et al. Prognosis of patients with hepatocellular carcinoma and portal vein tumor thrombus treated with combination of transarterial chemoembolization and palliative thermal ablation J . Int J Hyperthermia, 2022,31):97-107.27 Long J, Zheng JSZ Sun B, et aL Microwave ablation of hepatocellular carcinoma with portal vein tumor thrombosis after transarterial chemoembolization: a prospective study J . Hepatol Int, 2016,10(1):175-184.28 Xi Mz Zhang Lz Zhao L, et aL Effectiveness of stereotactic body radiotherapy for hepatocellular carcinoma with portal vein and/or inferior vena cava tumor thrombosis J . PloS One, 2013,8(5):e63864.29 Feng M, Suresh K, Schipper MJ, et al. Individualized adaptive stereotactic body radiotherapy for liver tumors in patients at high risk for liver damage: A phase 2 clinical trial J . JAMA Oncol, 2018,4(1):40-47.30 Huo YR, Eslick GD. Transcatheter arterialchemoembolization plus radiotherapy compared with chemoembolization alone for hepatocellular carcinoma: A systematic review and meta-analysis J . JAMA Oncol, 2015Z 1(6): 756-765.31 Li XL, Guo WX, Hong XD, et al. Efficacy of the treatment of transarterial chemoembolization combined with radiotherapy for hepatocellular carcinoma with portal vein tumor thrombus: A propensity score analysis J . Hepatol Res, 2016,46(11):1088-1098.32 苏庭世，梁世雄,黎建绪，等.基于倾向性匹配对比外科手术与肝动 脉化疗栓塞联合放疗治疗肝癌合并门静脉癌栓效果研究J .中国实用外 科杂志,2021,47):786-790,794.33 Choi JHZ Chung WJ, Bae SHZ et aL Randomized, prospective, comparative study on the effects and safety of sorafenib vs. hepatic arterial infusion chemotherapy in patients with advanced hepatocellular carcinoma with portal vein tumor thrombosis J 1 Cancer Chemother Pharmacol, 2018,82(3):469-478.34 Katamura Y, Ai kata H, Ta kaki S, et al. Intra-arterial 5-fluorouracil/interferon combination therapy for advanced hepatocellular carcinoma with or without three-dimensional conformal radiotherapy for portal vein tumor thrombosis J . J Gastroenterol, 2009,44(5):492-502.35 Onishi H, Nouso K, Nakamura S, et al. Efficacy of hepatic arterial infusion chemotherapy in combination with irradiation for advanced hepatocellular carcinoma with portal vein invasion J . Hepatol Int, 2015,9(1):105-112.36 Vibert Ez Azoulay D, Cunha AS, et al. Portal stenting for hepatocellular carcinoma extending into the portal vein in cirrhotic patients J . J Surg Oncol, 2013,107(7):696-701.37 Luo JJ, Zhang ZH, Liu QXZ et aL Endovascular brachytherapy combined with stent placement and TACE for treatment of HCC with main portal vein tumor thrombus J . Hepatol Int, 2016,10(1):185-195.38 Li Z, Si G, Jiao DC, et al. Portal vein stenting combined with (125)1 particle chain implantation followed by As2O3 in the treatment of hepatocellular carcinoma with portal vein tumour thrombus J . Biomed Res Int, 2020,2020:4109216.39 吴林霖，颜志平，等.经动脉灌注化疗联合(125)1粒子条治疗原发性肝癌合并门脉癌栓的疗效分析J .介入放射学杂 志,2015,24(9):776-780.40 Zhang X, Wang K, Wang M, et al. Transarterial chemoembolization (TACE) combined with sorafenib versus TACE for hepatocellular carcinoma with portal vein tumor thrombus: a systematic review and meta-analysis J . Oncotarget, 2017,8(17):29416-29427.41 Hu H, Duan Z, Long X, et al. Sorafenib combined with transarterial chemoembolization versus transarterial chemoembolization alone for advanced-stage hepatocellular carcinoma: a propensity score matching study J . PloS One, 2014,9(5):e96620.42 Meng XCZ Chen BHZ Huang JJ, et aL Early prediction of 合并PVTT病人中的临床应用，将PVTT分为A型和B型，与肝切除术的 预后相关。对于指导临床决策及病人临床收益而言，局部治疗策略在不可切 除性HCC合并PVTT病人中因PVTT分型及肝功能状态而有所不同，根 据中国肝细胞癌合并门静脉癌栓诊疗指南（2021年版）7 总结局部 治疗的选择方式。2 局部治疗2.1 经动脉化疗栓塞术 在过去的20年中以及BRIDGE研究报告 显示，在包括来自全球14个国家，42个地区的18031例病人（亚洲病 人占全球的67% ）中,经动脉化疗栓塞术（transarterial chemoembolization ,TACE ）是BCLC C期病人最常见的治疗方法8 1一项回顾性研究结果显示，TACE组较保守治疗组的总生存期明 显延长（8.7个月个月）9 另一项多中心回顾性研究结果显示， TACE组较保守组在HCC合并PVTT I、口、m型中有较长的生存期, 而在PVTT IV型中并无临床收益;因此不推荐TACE用于HCC合并PVTT IV型的病人101在我国，HCC合并PVTT病人的治疗中，门静脉血管 内M25近程放疗具有很好的治疗效果，占据重要地位，也是具有中国特 色的治疗方式。例如:与单纯TACE治疗方式相比,TACE联合血管内1-125 粒子或粒子条植入治疗HCC合并PVTT病人是安全、可行、有效的11-12 1 survival in hepatocellular carcinoma patients treated with transarterial chemoembolization plus sorafenib J . World J Gastroenterol, 2018,24(4):484-493.43 Vilgrain 4 Pereira H, Assenat E, et al. Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial J . Lancet Oncol, 2017,18(12):1624-1636.44 Chow PKH, Gandhi M, Tan SB, et al. SIRveNIB: Selective internal radiation therapy versus sorafenib in asia-pacific patients with hepatocellular carcinoma J . J Clin Oncol, 2018,36(19):1913-1921.45 Giorgio A, Merola MG, Montesarchio Lz et al. Sorafenib combined with radio-frequency ablation compared with sorafenib alone in treatment of hepatocellular carcinoma invading portal vein: a western randomized controlled trial J . Anticancer Res, 2016,36(11):6179-6183.46 Zheng Kz Zhu X, Fu S, et aL Sorafenib plus hepatic arterial infusion chemotherapy versus sorafenib for hepatocellular carcinoma with major portal vein tumor thrombosis: A Randomized Trial J . Radiology, 2022,303(2):455-464.47 Goyal Lz Zheng Hz Abrams T Az et al. A phase II and biomarker study of sorafenib combined with modified FOLFOX in patients with advanced hepatocellular carcinoma J . Clin Cancer Res, 2019,25(1):80-89.48 Kim BK, Kim DY, Byun HKZ et al. Efficacy and safety of liver-directed concurrent chemoradiotherapy and sequential sorafenib for advanced hepatocellular carcinoma: a prospective phase 2 trial J . Int J Radiat Oncol Biol Phys, 2020,107(1):106-115.49 Li Sz Li L, Li B, et al. Safety and efficacy of endovascular implantation of a portal vein stent combined with iodine-125 seed-strips followed by transcatheter arterial chemoembolization with sorafenib for the treatment of hepatocellular carcinoma with portal vein tumor thrombosis J . Br J Radiol, 2020,93(1112):20190279.50Chang X, Lu X, Guo J, et al. Interventional therapy combined with immune checkpoint inhibitors: Emerging opportunities for cancer treatment in the era of immunotherapyJ . Cancer Treat Rev, 2019,74:49-60.51 Ding M, Wang Yz Chi Jz et aL Is Adjuvant cellular immunotherapy essential after TACE-predominant minimally-invasive treatment for hepatocellular carcinoma? a systematic meta-analysis of studies including 1774 patients J . PloS One, 2016,11(12):e0168798.52 Li JX, Su TSZ Gong WF, et al. Combining stereotactic body radiotherapy with camrelizumab for unresectable hepatocellular carcinoma: a single-arm trial J . Hepatol Int, 2022,16:1179-1187.53 Cai M, Huang W, Huang J, et al. Transarterial chemoembolization combined with lenvatinib plus pd-1 inhibitor for advanced hepatocellular carcinoma: a retrospective cohort study J . Front Immunol, 2022,13:848387.同时,Hong等13 研究结果显示,超声引导下经皮1-125粒子近程放疗 联合TACE治疗HCC合并Vp1及Vp2型PVTT病人的总体生存获益更加 显著（中位总生存期：13个月个月X亦有研究应用M 25粒子螺 旋系统序贯肿瘤同侧分支癌栓粒子植入联合TACE治疗HCC合并PVTT ID型病人，结果显示安全可行14故单用TACE及TACE联合门静脉 血管内1-125近程放疗治疗HCC合并PVTT I、口、m型（门静脉存在 侧支循环或非完全阻塞）、肝功能良好的病人具有优势。未来还需要更多 的研究筛选出适合TACE治疗的病人，以获得最大生存期。2.2 经动脉放射栓塞术目前，经动脉放射栓塞术（transarterialradioembolization , TARE ）在HCC病人中的疗效仍存在争议。一些研 究者认为，TARE与TACE相比有相似的疗效，甚至超过后者，使病人获 得最大的临床获益。Kooby等15 研究发现TARE与TACE相比（中位 总生存期：6个月vs. 6个月）在不可切除病灶的HCC病人中具有相似的 疗效。TARE与TACE治疗合并PVTT的HCC病人相比，发生血管内严重 缺血的情况明显减少，这也是TARE用于治疗该类病人的优势3 早期 一些研究也认为TARE可提高HCC合并PVTT病人的生存获益16-18 1 近年来的一项Meta分析结果表明，与索拉菲尼组相比，TARE治疗合并 PVTT的HCC病人更安全、更有效（0.5年、1年生存率分别为:76%vs.56%、 47%vs.24% ）19L同时最新的美国国家综合癌症网络（NCCN ）指南 指出，TARE可能更适用于节段性PVTT病人的治疗。近年来提出个体化剂量测定的新概念，也称增强选择性内部放射 治疗（boost selective internal radiotherapy , B-SIRT ）0与标准剂量 TARE的治疗方式相比，B-SIRT可使肝脏肿瘤受到更高剂量的辐射（ 205Gy vs. 205Gy ），同时肝脏的副反应并未显著增力口 20 1 Hermann 算21 研究结果表明应用个体化剂量TARE的方式治疗HCC合并PVTT 病人的生存期可明显延长，随着应用剂量的变化生存期也有所改变（ 100Gy14.1个月vs. 100Gy6.1个月工其中接受最佳剂量治疯 10OGy ） 病人的中位总生存期为24.9个月。Mazzaferro等22 认为TARE治疗 HCC合并Vp1Vp4型PVTT病人是安全有效的，且肿瘤反应与目标靶 区的剂量显著相关，其中500Gy是预测肿瘤反应的阈值。随着RCT、回顾性研究以及前瞻性研究的不断深入,个性化剂量 测定新方法的出现与成熟以及术者熟练程度的不断提高，未来在我国 TARE可能是替代TACE治疗HCC合并PVTT I、口、m型病人的新方法。2.3 消融术 消融术（ablation ）被认为是肿瘤直径 3 cm的早期 HCC病人的临床一线治疗方法23 1大部分临床实践指南，包括美国临 床肿瘤学会（ASCO ）、NCCN、欧洲医学肿瘤学会（ESMO ）、中国临床 肿瘤学会（CSCO ）指南推荐早期HCC病人（BCLC 0A期）进行消融治 疗，可达到临床治愈的目的24 1，在Giorgio等25 的研究结果表明, PVTT经消融术治疗后门静脉完全复通率可达77%，提示消融术可能对门 静脉复通率具有优势。Zhou等26 研究结果发现，TACE联合姑息性 热消融（palliative thermal ablation ）与单用TACE治疗相比,可提高PVTT I、口、m型病人的生存率、提高总生存率(0.5年、1年、1.5年 总生存率分别为 70.9%、46.5%、31.0%vs.57.0%s23.1%、10.0% )o 而Long等27 研究结果表明，TACE术后联合微波消融(microwa