修回日期: 2021-03-30
接受日期: 2021-04-23
在线出版日期: 2021-05-28
原发性肝癌发病隐匿, 早期无特异性症状, 多数患者确诊时已属中晚期, 符合根治性切除术的患者20%-40%. 目前外科切除仍是原发性肝癌主要根治性治疗手段, 但由于肝功能失代偿、肿瘤体积过大、剩余肝体积过小、肝内多发转移、癌栓侵及大血管或胆管、远处转移等因素限制手术切除或肝移植. 近年来, 随着原发性肝癌发生、发展机制研究的不断深入, 外科技术和器械发展, 以及新的分子靶向药物、免疫治疗药物的研制, 使得一部分无法手术切除或肝移植的原发性肝癌患者经过转化治疗, 改善肝功能、缩小肿瘤体积、使脉管癌栓缩小或消失、促进剩余肝脏体积代偿性增大, 最终得以手术切除或肝移植, 极大提高了原发性肝癌治疗效果和患者生存期.
核心提要: 由于剩余肝体积过小、肝内多发转移、肿瘤侵及大血管或胆管、远处转移等因素限制原发性肝癌手术切除或肝移植.转化治疗使一部分无法手术的原发性肝癌患者最终实施手术切除或肝移植,提高了原发性肝癌疗效和患者生存期.
引文著录: 秦建民. 原发性肝癌转化治疗指征与选择策略. 世界华人消化杂志 2021; 29(10): 501-510
Revised: March 30, 2021
Accepted: April 23, 2021
Published online: May 28, 2021
Primary liver cancer has an insidious onset and no specific symptoms at early stage. Most patients are in the middle or advanced stage when diagnosed, and only 20%-40% of patients meet the criteria for radical resection. At present, surgical resection is still the main radical treatment for primary liver cancer, but factors such as liver function decompensation, too large tumor volume, too small future liver remnant, intrahepatic multiple metastasis, tumor thrombus invading the large vessels or bile duct, and distant metastasis limit the application of surgical resection or liver transplantation. In recent years, with the advances of basic research of primary liver cancer, the development of surgical techniques and equipment, as well as the development of new molecular targeted drugs and immunotherapy drugs, a part of unresectable patients with primary liver cancer can receive conversion therapy to improve liver function, minimize tumor volume, minimize or inactivate tumor thrombus, and increase the residual liver volume. Following conversion therapy, patients with primary liver cancer can undergo surgical resection or liver transplantation, which greatly improve the therapeutic efficacy and patient survival.
- Citation: Qin JM. Conversion therapy for primary liver cancer: Indications and selective strategies. Shijie Huaren Xiaohua Zazhi 2021; 29(10): 501-510
- URL: https://www.wjgnet.com/1009-3079/full/v29/i10/501.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v29.i10.501
原发性肝癌(primary liver cancer, PLC)是常见的肝脏恶性肿瘤, 其发病率和死亡率在全球癌症排名第7位和第3位, 其中, 肝细胞癌(hepatocellular carcinoma, HCC)占75%-85%, 肝内胆管细胞癌(intrahepatic cholangiocarcinoma, ICC)占10%-15%, 发病隐匿, 早期无特异性症状, 多数患者虽然确诊时已属中晚期, 随着外科技术的进步, 手术切除率显著提高20%-40%, 但术后复发率仍然较高为40%-80%[1,2]. 目前外科切除仍是PLC主要根治性治疗手段, 但由于肿瘤体积过大、剩余肝体积过小、肝内多发转移、癌栓侵及大血管或胆管、远处转移等因素限制手术切除或肝移植, 若强行肝切除或肝移植, 极大增加术后高复发、转移与肝衰竭发生风险[3]. 近年来, 随着PLC发生、发展机制研究的不断深入, 外科技术和器械发展, 以及新的分子靶向药物、免疫治疗药物的研制, 使得一部分无法手术切除或肝移植的肝脏肿瘤经过个体化的治疗得以手术切除或肝移植, 极大提高了PLC治疗效果和生存期. 转化治疗(conversion therapy)是因肝功能差(Child-Pugh C级)、肺转移、门静脉癌栓、肿瘤播散或多发、肿瘤巨大等因素不能行根治性手术切除或肝移植, 但具有潜在手术切除或肝移植的PLC患者, 经积极内科治疗(保肝、分子靶向、免疫、化疗等)联合局部介入、放疗等治疗后, 使患者肝功能转为Child-Pugh A或B级, 控制肿瘤进展, 降低临床分期, 从而获得手术切除或肝移植机会[4,5]. 转化治疗不同于术前新辅助治疗, 前者治疗的目的在于改善肝功能、缩小肿瘤体积、促使脉管癌栓缩小或消失、促进剩余肝脏体积代偿性增大, 为PLC患者创造手术切除或肝移植机会. 后者是指有手术指征的PLC患者, 经术前治疗后减小肿瘤, 增加R0切除率, 降低远处转移和复发率, 提高PLC患者的生存. 本文结合相关文献, 探讨PLC转化治疗指征与选择策略.
依据患者肝功能、肿瘤体积、脉管癌栓、未受累肝脏体积等情况, 确定PLC转化治疗的指征[3]: (1)肝功能损害, Child-Pugh C级; (2)肿瘤巨大, 根治性切除后剩余肝体积不足(无肝硬化者, 剩余肝体积/标准肝体积＜20%-30%, 合并肝硬化、重度脂肪肝和化疗或梗阻性黄疸引起的肝损伤者, 剩余肝体积/标准肝体积＜40%); (3)肿瘤合并大血管癌栓, 如门静脉主干或一级分支癌栓、合并下腔静脉癌栓, 难以完全取净癌栓, 具有肝内外播散风险; (4)肿瘤多发, 分布在多个肝叶, 难以根治性切除; (5)肿瘤合并肺、局部淋巴结多发转移, 无全身广泛肿瘤转移; (6)肿瘤侵犯3支肝静脉或左右门静脉主干, 难以完成肿瘤根治性切除. 因此原发性肝癌转化治疗期间, 需要采用超声、超声造影、增强CT和/MRI、PET-CT/MRI等合适的影像技术, 结合血肝功能、肿瘤标记物(AFP、DCP、CA19-9)、病理学检查等进行综合评估, 评价ECOG评分、剩余肝体积、肿瘤大小、数目、坏死、癌栓大小与分布、血肿瘤标记物水平等, 监测肿瘤对转化治疗的反应率, 适时评估肿瘤临床分期及转化治疗效果.
转化治疗后手术切除或肝移植指征[6-8]: (1)无肝硬化背景肝病患者功能性剩余肝体积≥标准肝体积的35%, 具有肝硬化背景的患者功能性剩余肝体积≥标准肝体积的45% , 肿瘤切缘＞2 cm; (2)肝功能储备吲哚菁绿15 min滞留率≤20% ; (3)肝功能Child-Pugh分级为A/B级; (4)ECOG评分为0-1分; (5)MRI与PET-CT提示大血管内癌栓失活, 累积3支肝静脉或左右门静脉主干的肿瘤退缩, 能够完成肿瘤根治性切除; (6)符合米兰或UCSF标准. 原发性肝癌转化治疗后增加机体接触肿瘤新抗原的时间可能会导致通过免疫治疗激活的T细胞重新进入功能障碍状态, 从而增加肿瘤再次进展的可能[6,9], 因此不可手术切除或肝移植的原发性肝癌经转化治疗达到部分或完全缓解符合上述手术指征时均需适时进行手术切除或肝移植治疗, 以免错过最佳的手术治疗时机. 成功转化治疗的最终目标是降低肿瘤分期, 增加剩余肝体积, 提高挽救性手术率, 但不增加手术并发症、死亡率.
原发性肝癌转化治疗的目的是使肝内、外部分肿瘤消失、巨大肿瘤体积缩小、静脉或胆管癌栓缩小、消失或灭活、未受肿瘤累及的肝脏代偿性增大, 增加患者手术切除或肝移植机会. 目前转化治疗的方法包括: (1)肝功能维护; (2)未受累肝脏体积代偿性增大(联合肝脏分割和门静脉结扎的分阶段肝切除术、门静脉栓塞术等); (3)肿瘤体积缩小、脉管癌栓缩小或灭活(包括介入治疗、放疗、分子靶向药物、免疫治疗等), 转化治疗方法的选择取决于患者肝功能、肝脏肿瘤的位置、大小、数目、血供、血管或胆管癌栓分布、未受累肝脏体积等情况, 制定合适的转化治疗方案.
HCC患者多数合并乙型或/和丙型肝炎病毒感染, 或长期饮酒引起肝硬变, ICC患者多合并肝内胆管结石、肿瘤累及胆管致胆汁淤积引起肝功能损害, 均导致肝功能失代偿(Child-Pugh评分C级), 使患者出现低蛋白血症、凝血功能紊乱、高胆红素血症、骨髓造血功能障碍(贫血、中性粒细胞减少、血小板减少等), 不能耐受手术切除、介入治疗及放疗等治疗. 因此维护和改善患者肝功能, 是原发性肝癌转化治疗的重要一环, 需要戒烟酒, 停止接触肝毒性药物, 给予高热量、高蛋白质、低脂肪饮食, 静脉补充葡萄糖、维生素、氨基酸等, 肝内胆汁淤积给予熊去氧胆酸, 肝细胞炎症应用甘草酸二胺、多烯磷脂酰胆碱等保肝药物. 乙肝病毒相关肝癌患者即使HBV-DNA浓度＜2×103/L, 处于低水平状态, 亦应给予抗病毒治疗, 若合并TBil或ALT升高, 同时给予保肝和利胆治疗, 改善肝功能, 以减少术后肝功能失代偿和肿瘤复发[10]. 胆管梗阻患者血总胆红素＞200 µmol/L需要及时给予胆汁内/外引流, 严重低蛋白血症者给予输新鲜血浆或人血白蛋白, 辅助肝细胞修复和再生, 补充维生素K1, 纠正凝血功能紊乱; 合并食管胃底静脉曲张者口服卡维地洛降门静脉压力, 腹腔积液引起腹内压增高者适当引流腹水、利尿剂治疗. 经过内科转化治疗适时评估肝功能、肝脏储备功能, 一旦肝功能达到Child-Pugh评分A或B级, 及时行手术切除、介入治疗或放疗等治疗.
许多原发性肝癌患者因肿瘤巨大毗邻重要脉管结构需行大范围肝切除, 导致剩余肝脏体积(future 1iver remnant, FLR)不足而无法行一期根治性切除, FLR不足是影响肝切除术后肝功能衰竭和围手术期死亡的决定性因素[11]. 保证足够的FLR是决定肝肿瘤切除手术的关键因素之一, 目前主要用于增大FLR体积方法包括联合肝脏分割和门静脉结扎的分阶段肝切除术(associating liver partition and portal vein ligation for staged hepatectomy, ALPPS)和门静脉栓塞术(portal vein embolization, PVE), ALPPS术通过阻断患侧肝脏的门静脉主干及健侧肝脏来源的交通支, 使健侧肝脏获得足够的门静脉血流和营养物质, 术后1-2 wk左右诱导FLR增生率高达47％-192％, 日增生体积高于PVE(4.4 mL/d±4.8 mL/d vs 3.66 mL/d±2.2 mL/d), 且两期手术间隔时间短(术后2 wk左右), 能最大程度减少肿瘤进展风险, 肿瘤切除率达95％-100％, 高于PVE(66％)[12-14]. Wang等[15]计划实施ALPPS治疗初期不可切除的原发性肝癌, 第一期手术使残余肝体积增加了56.8%, 82%患者成功完成了第二期手术, 1年、3年总生存率分别为64.2%和60.2%, 但ALPPS属于创伤较大手术, 且短时间内需要进行两次手术, 术后胆漏发生率为20％-24％, 术后感染发生率为20％-23％ , 术后肝功能衰竭发生率高达15％-22％[16,17], 虽然目前有一些改良的ALPPS技术(如绕肝提拉带、射频或微波辅助ALPPS, 腹腔镜或机器人辅助ALPPS等)在一定程度上减少了ALPPS术创伤和围手术期并发症[18-21], 但对肝癌患者仍然带来较大的创伤, 因此应严格限制原发性肝癌患者ALPPS术应用指征: 年龄＜60岁, 肝功能正常(Child-Pugh A级, ICG-R15＜10％), FLR不足(正常肝脏, FLR/SLV＜30％; 伴有慢性肝病和肝损伤, FLR/SLV＜40％), 一般状态良好, 无严重肝硬化、脂肪肝和门静脉高压症[22-24], 在实施ALPPS时, 如果二期术前患者MELD评分＞10分者建议延迟第二步手术[25], 加强围手术期机体脏器功能维护, 积极处理并发症, 降低围手术期死亡率.
PVE技术采用经皮穿刺应用钢圈或a-氰基丙烯酸正丁酯(N-butyl a-cyanoacrylate, NBCA)胶等栓塞剂栓塞患侧门静脉, 诱导健侧肝脏组织增生, PVE治疗4周后患者肝脏体积总体增加10%-12%, 二期肝切除成功率为60％-80％, 并发症发生率约10％-20％[26-28]. 与ALPPS相比, PVE后栓塞对侧肝脏增生时间相对较长(4-6 wk), 在此期间20％以上患者因肿瘤进展或FLR增生体积不足而失去手术机会[29,30]. 为克服PVE缺点, Peng等[31]采用NBCA胶栓塞患侧门静脉及末梢分支, 使其兼具ALPPS肝脏快速增生和PVE的微创效应, 二期肝切除率提高至84％左右, 平均等待时间缩短至2-3 wk. PVE联合肝动脉栓塞化疗(transarterial chemoembolization, TACE)能进一步促进FLR增生率(12％), 显著高于单用PVE(8％), 能够更好地控制肿瘤进展, 提高肿瘤切除率(97％), 显著提高5年存活率(43％-72％), 降低5年肿瘤复发率(37％-61％)[32,33]. PVE联合肝静脉栓塞(hepatic vein embolization, HVE)显著诱导FLR增生(28.9％), 优于单独PVE增生率(13.3％), 3年存活率为45.1％[28,34]. 与ALPPS相比, PVE具有较小创伤, 但并非适合于任何原发性肝癌患者, 对于栓塞侧门静脉有癌栓, 肿瘤广泛转移, 合并严重的门静脉高压症和凝血功能障碍等肝癌患者禁忌[35]. 当剩余肝脏体积＜30%时宜行ALPPS, 当剩余肝脏体积＞30%且＜40%时宜行PVE[36]. 因此对于FLR不足的原发性肝癌患者, 应结合患者年龄、肿瘤、机体脏器功能等情况, 选择合适的增加FLR体积的方法, 适时进行影像学评估, 及时进行肝肿瘤切除.
对于肿瘤负荷大或大血管、胆管癌栓无法根治性切除/肝移植的PLC患者, 如果不进行积极地治疗, 患者预后极差, 晚期HCC患者门静脉癌栓(portal vein tumor thrombus, PVTT)发生率高达44%-62.2%, 胆管癌栓为1.2%-9%[37,38], 合并PVTT, 中位生存时间为2-4 mo, 合并肝静脉或下腔静脉癌栓, 自然病程1-8 mo, 合并胆管癌栓, 中位生存4.3 mo[39-41]. 因此对于此类肝癌患者需要采取积极的治疗方法, 争取手术切除或肝移植机会, 延长患者生存期.
2.3.1 全身化疗: 不可手术切除的晚期HCC患者应用FOLFOX4方案全身化疗, 与单用阿霉素相比, 患者中位无进展生存期(median progression-free survival , mPFS)分别为2.93 mo和1.77 mo, 客观反应率(objective response rate, ORR)分别为8.15％和2.67％, 总生存期(overall survival, OS)分别为6.47 mo和4.9 mo[42]. Kaseb等[43]对84例不可切除性HCC患者采用顺铂、阿霉素、5-氟尿嘧啶和IFNα-2b联合治疗方案, 其中33％患者转化治疗后行根治性肝肿瘤切除. 雷替曲塞联合奥沙利铂方案较FOLFOX4方案对晚期原发性肝癌的疾病控制率(disease control rate, DCR)显著提高(56.76％ vs 40.54％)[44]. Zaanan等[45]采用GEMOX化疗方案(吉西他滨联合奥沙利铂)治疗进展期HCC, 8.5％患者成功降期后行肝肿瘤根治性切除. Le等[46]采用吉西他滨联合奥沙利铂治疗74例不可切除的ICC, 6个疗程后39例(53%)患者成功转化手术切除. 表明随着高效化疗药物的研制和联合临床应用, 在晚期原发性肝癌转化治疗中发挥重要的治疗作用.
2.3.2 介入治疗: TACE通过破坏肿瘤血供从而诱导肿瘤缺血, 化疗药物通过肿瘤血管直接注入肿瘤组织, 形成肿瘤组织局部高浓度药物环境, 碘油栓塞肿瘤滋养末梢血管, 协同抑制肿瘤生长, 已成为进展期肝癌治疗的主要方法之一. 但由于碘油清除过快, 达不到长久栓塞的目的, 同时药物在碘化油中迅速释放, 不能在肿瘤组织内长时间保持较高浓度, 导致TACE术后肿瘤完全坏死比例相对较低(1.7％-6.6%)[47]. Fan等[48]采用TACE治疗不可手术切除HCC患者转化为肝脏肿瘤切除率为18.1%. 药微球能够吸附化疗药物, 使化疗药物持续地作用于肿瘤内部, 而且微球在体内不降解, 能长久栓塞肿瘤血管, 进一步提高TACE的疗效, 王浩等[49]术前应用携载表柔比星药物洗脱微球肝动脉栓塞治疗进展期肝癌, 76.7%患者降期至符合UCSF标准, 53.3%患者降期至符合米兰标准, 成功降期后进行了肝移植. Affonso等[50]术前采用载药微球肝动脉栓塞治疗超过米兰标准肝癌患者, 34.4%患者成功降期后行肝移植, 与符合米兰标准的肝癌患者相比, 肝移植术后OS(73.5％ vs 72.3％)和无瘤生存率(62.1％ vs 74.8％)无显著性差异. TACE治疗的局限性在于栓塞术后肿瘤微环境改变, 缺氧诱导因子上调, 使血管内皮细胞和血小板源生长因子增加, 诱导肿瘤新生血管的形成, 导致肿瘤生长、肝外转移等不良结果而影响疗效[51,52]. 因此TACE联合酪氨酸激酶受体抑制剂索拉非尼能够抑制肿瘤细胞增殖和血管新生, 14.8%患者成功转化实施肝肿瘤切除, 术后1、2、3年的无瘤存活率分别为76.2% 、52.4% 、43.6%[53]. 肝动脉灌注化疗(hepatic arterial infusion chemotherapy, HAIC)与传统的TACE不同, HAIC以肿瘤滋养动脉持续灌注以奥沙利铂为主的化疗药物(如FOLFOX方案、GEMOX方案等)48-72 h, 使局部肿瘤组织持续维持高浓度化疗药物, 提高化疗药物杀灭肿瘤效果. Lee等[54]应用HAIC治疗进展期HCC患者, 11.7%患者转化后行肝肿瘤切除, 中位OS为(37±6.6) h. HAIC 联合索拉非尼治疗合并有门静脉分支或主干癌栓的HCC患者, 6.48%患者转化成外科手术切除, 优于单用索拉非尼治疗(0.4%), 且联合治疗患者中位OS 为13.37 mo, PFS为7.03 mo, 优于单纯索拉非尼治疗中位OS(7.13 mo), PFS为2.6 mo[55]. HAIC联合三维适形放疗治疗HCC合并门静脉癌栓患者, 有效率为61.5%, 17.3%不能手术切除的HCC患者转化为手术切除, 术后1、2、3年OS分别为100%、100%、71%, 优于非手术患者(50%、20%、18%)[56]. Chong等[57]采用放疗联合肝动脉灌注5-氟尿嘧啶治疗HCC合并门静脉一级分支或二级分支癌栓的患者, 26.5%患者降期转化后再手术切除, 术后中位生存期显著优于直接手术的患者(62 mo vs 15 mo). Massani等[58]应用HAIC(5-FU+奥沙利铂)治疗11例不可切除ICC患者, 4-12个周期(平均8个周期)后3例(27.3%)进行肝肿瘤切除, 术后病理证实70%肿瘤发生坏死. 经肝动脉放疗栓塞(transarterial radioembolization, TARE)是将载有发射β射线的钇-90(90Y)玻璃微球选择性注入肝动脉, 放射性微球因无法通过肿瘤的毛细血管床而聚集在肿瘤组织, 其发出的β射线对靶肿瘤具有细胞毒性作用, 由于β射线在肝组织内的穿透能力只有2.5 mm, 在杀伤肿瘤细胞的同时对正常肝脏组织损伤较小[59]. TARE后57% HCC患者肿瘤缩小, 因门静脉癌栓对放疗较为敏感, 癌栓内的癌细胞能被β射线迅速杀灭, 即使术中癌栓内癌细胞脱落到正常肝脏, 由于癌细胞活性降低, 难以增殖存活, 对门静脉癌栓具有显著的治疗作用[60]. Lau等[61]采用90Y微球联合PIAF化疗方案(顺铂+密拓蒽醌+5-氟尿嘧啶+干扰素)治疗不能切除HCC, 17.8%患者成功降期接受手术切除, 5年生存率为57%. 不可切除的ICC, 10.8%-21.6%患者经90Y 微球TARE转化治疗后接受肝肿瘤切除[62,63]. 由于放疗对肿瘤细胞杀伤作用的滞后性, TARE治疗3-6 mo后肿瘤坏死范围仍会增加, 因此中晚期原发性肝癌患者行TARE后肿瘤对TARE的应答率高于TACE(61％ vs 37％), TARE治疗后降期接受手术成功率高于TACE(58％ vs 31％)[64]. Tabone等[65]应用90Y微球TARE治疗24例合并门静脉癌栓不可手术HCC患者, 5例(20%)转化后接受肝肿瘤切除, 术后中位OS为30个月. Riby等[66]应用90Y微球TARE治疗19例不可切除ICC, 100%成功降期接受肝肿瘤切除, 术后中位OS与I期手术切除ICC相似(32.3 mo vs 45.9 mo). Labgaa等[67]应用TARE治疗319例不能手术切除HCC, 10.03%患者降期成功后行根治性手术, 其中22例行肝移植术, 10例行肝肿瘤切除, 术后中位OS超过41.5 mo. 临床研究表明针对不同患者选择TACE、HAIC、TARE等局部介入治疗是进展期原发性肝癌降期转化治疗的重要治疗方法之一.
2.3.3 放疗: 三维适形放疗采用精准定位肿瘤靶区发射X射线使癌细胞核的DNA 链发生断裂, 抑制癌细胞增殖分裂、杀灭癌细胞, 不能手术切除的HCC患者经体外放疗后, 23％患者转化为二期手术切除[68]. Assalino等[69]对侵犯大血管的HCC进行治疗, 局部放疗能够控制肿瘤负荷、缩小肿瘤体积, 66.7%患者经局部放疗后血管浸润完全消退, 成功接受肝移植术. 立体定向放射治疗(stereotactic body radiation therapy, SBRT)治疗HCC合并PVTT侵犯门静脉右支、左支或主干, 12例患者获得PVTT降期(PVTT从程式分型的Ⅲ型降至Ⅱ型或从Ⅱ型降至I型), 新辅助放疗联合肝肿瘤切除术后1年、1.5年和2年的OS分别为75.2%、43.9%和27.4% , 优于单纯手术切除43.1%、16.7%和9.4%[70]. Yeh等[71]回顾性分析106例合并PVTT的HCC患者接受调强放疗, 其中癌栓位于门静脉主干30例次, 门静脉右支71例次, 门静脉左支37例次, 12例(11.3%)患者成功降期接受手术切除, 2年总生存率为66.7%, 中位OS为30 mo, 显著优于未能手术切除的患者. 提示门静脉癌栓对放疗较为敏感, 癌栓内癌细胞能迅速被X射线杀伤或灭活, 即使术中癌栓内癌细胞脱落到剩余肝脏, 由于癌细胞活性降低使其难以增殖存活, 降低了术后复发风险. Shui等[72]对门静脉广泛癌栓无法手术的HCC患者行SBRT治疗, 5.7％患者成功降期转化接受肝肿瘤切除. 采用放疗联合肝动脉灌注5-氟尿嘧啶化疗治疗合并PVTT的HCC, 放疗靶区包含门静脉癌栓和肝脏肿瘤, 13.2%患者成功降期接受肝肿瘤切除, 术后5年生存率为49.6%, 未切除患者仅为9.8%[73]. TACE联合放疗不可切除HCC患者, 11.1%患者成功转化接受肝肿瘤切除[74]. Sumiyoshi等[75]应用调强放疗联合S-1治疗7例不可手术的ICC患者, 5例患者(71.4%)进行肝肿瘤切除, 术后生存6-58 mo(平均28.8 mo). 肝脏肿瘤及血管/胆管癌栓进行局部放射治疗, 不仅能够控制肿瘤生长, 而且能够缩小或灭活癌栓, 提高进展期原发性肝癌患者的手术切除率或肝移植机会, 尤其联合介入治疗、分子靶向药物等方法能够显著提高转化治疗效率.
2.3.4 分子靶向药物治疗: Ras/Raf/Mek/ERK、Pl3K/Akt/雷帕霉素靶蛋白(mTOR)等信号通路相关分子、血管内皮生长因子受体(vascular endothelial growth factor receptor, VEGFR)、血小板源性生长因子受体(platelet-derived growth factor receptor, PDGFR)和表皮生长因子受体(epithelial growth factor receptor, EGFR)等在肝癌组织中过表达, 参与肿瘤细胞增殖、侵袭, 在原发性肝癌发生、发展过程中具有重要生物学作用, 亦是原发性肝癌分子靶向药物治疗的分子基础[76,77]. 分子靶向药物是针对肿瘤的特异性分子靶点设计的有针对性地抗肿瘤治疗, 具有特异性强、正常组织细胞损伤小等优点, 近年来研制的分子靶向药物(如索拉非尼、乐伐替尼、瑞戈非尼、卡博替、雷莫芦单抗等)在原发性肝癌治疗中发挥重要的作用, 并取得了较好的疗效. 研究表明成纤维细胞生长受体4(fibroblast growth factor receptor 4, FGF4)是索拉非尼治疗反应的一个新的候选生物学标志物, FGF4阳性的HCC患者应用索拉非尼治疗具有显著的病理反应, 治疗前肿瘤FGFR4水平是索拉非尼、仑伐替尼等分子靶向药物治疗反应的预测因子[78,79]. Yoshimoto等[78]应用索拉非尼治疗2例FGFR4阳性不可切除HCC患者, 治疗3 mo后, 成功实施肝肿瘤切除, 术后随访4.5年无肿瘤复发. Barbier等[80]应用索拉非尼治疗2例HCC合并PVTT患者经9 mo转化治疗后成功行肝肿瘤切除. Tanaka等[81]应用仑伐替尼治疗3例不可切除的HCC, 6 mo后2例行肝肿瘤切除术, 1例行微波消融肝肿瘤治疗, 术后随访10 mo未见肿瘤复发. 单一分子靶向药物治疗进展期HCC的ORR较低, 索拉非尼为2%, 仑伐替尼为24.1%[82,83], 因此需要与其它治疗方法(介入治疗、化疗、放疗等)结合, 以提高转化治疗效果. Vagefi等[84]应用索拉非尼联合局部肿瘤射频消融治疗超过米兰标准的HCC患者, 转化治疗后评估患者符合米兰标准成功进行了肝移植术. Gruenberger等[85]应用靶向EGFR的西妥昔单抗联合吉西他滨和奥沙利铂三药联合治疗不能切除的30例胆管癌患者, 5例ICC患者(16.7%)降期后接受手术切除肝肿瘤, 中位PFS为21.2个月. 分子靶向药物在进展期原发性肝癌治疗中发挥重要的作用, 依据高通量测序技术等检测肝癌组织和血液基因表达变化, 选择合适的分子靶向药物, 尤其联合介入治疗、放疗、化疗等治疗方法, 具有协同增效作用.
2.3.5 免疫治疗: 免疫功能障碍是肝癌发生和转移的重要因素, 免疫治疗通过调节特异性免疫反应抑制或杀死肿瘤细胞, 打破免疫耐受, 增强机体对肿瘤的免疫排斥反应, 延缓肿瘤进展, 降低肿瘤复发和转移的能力. 目前常用的免疫治疗方法如肿瘤疫苗(致敏树突状细胞疫苗和多肽疫苗)、过继性细胞疗法(NK、CIK、CTL、CAR-T细胞等)、免疫检查点抑制剂(immune checkpoint inhibitors, ICIs), CTLA-4抑制剂、PD-1、 PD-L1抑制剂等在肿瘤部位重新激活T细胞或抑制特异性T细胞的活化, 从而抑制肿瘤生长[86]. PD-1抑制剂卡瑞利珠单抗治疗进展期HCC, 中位OS为12.5 mo, ORR为13.8%, 6 mo总生存率为74.4%[87]. 单独使用免疫检查点抑制剂的有效率仅为10%-30%, 因此需要与其它治疗方法(介入治疗、放疗、化疗、分子靶向药物等)联合, 达到协同增效的作用[88]. 分子靶向药物(贝伐单抗)和PD-1抑制剂(阿替利珠单抗)联合应用治疗HCC应答率约为30%[89]. 纳武单抗(nivolumab, PD-1抑制剂)联合伊匹木单抗(ipilimumab, CTLA-4抑制剂)治疗不可手术切除的HCC患者, ORR为80%, DCR为100%[90]. Sun等[91]采用不同酪氨酸激酶抑制剂(阿帕替尼、仑伐替尼)加抗PD-1抗体(帕博利珠单抗、信迪利单抗等)治疗不可手术的HCC患者, 18.3%患者转化为手术切除切除, 5例术后病理证实完全缓解. 免疫治疗尤其免疫检查点抑制剂的研制和临床应用, 为进展期原发性肝癌治疗带来新的曙光, 依据肝癌组织、血液中肿瘤突变负荷(tumor mutation burden, TMB)、微卫星不稳定(microsatellite instability, MSI)、错配修复基因(mismatch repair, MMR)、γ-干扰素、肿瘤浸润淋巴细胞、PD-1和/PD-L1等表达变化, 选择不同免疫治疗方法, 且与分子靶向药物、放疗、化疗、介入治疗等方法的联合应用, 在原发性肝癌转化治疗中发挥越来越重要的作用.
原发性肝癌转化治疗能够缩小肿瘤, 但不能完全杀灭肿瘤细胞, 转化治疗后行手术切除肝肿瘤或肝移植, 术后肿瘤复发率为40％-80％[92,93]. 肿瘤直径＞5 cm、多发肿瘤结节无包膜、门静脉/肝静脉癌栓和微血管侵犯(microvascular invasion, MVI)等高危因素是肝癌患者术后肿瘤复发、转移的重要独立危险因素[94]. Wang等[95-97]在肝癌术后应用索拉非尼, 结果发现应用索拉非尼的HCC患者术后复发率明显低于对照组(29.4% vs 70.7%), 多因素分析提示索拉非尼是术后肿瘤复发的独立影响因素, 术后应用索拉非尼能够减少肿瘤复发, 显著改善患者PFS及OS. 对超越米兰标准HCC患者肝移植术后应用索拉非尼预后优于吉西他滨[98]. 对于具有高危因素的原发性肝癌患者术后积极序贯TACE治疗, 能够有效降低肿瘤复发率, 提高患者术后OS和无瘤生存率［99］. TACE和放疗对肝癌患者免疫系统部分或完全抑制, 促使HBV大量复制再激活, 再激活率达20%-30%, 尤其血清HBV DNA＞1.0×104拷贝/mL时, 增加HBV再激活和肿瘤术后复发风险[100,101], 因此转化治疗肝肿瘤切除或肝移植术后需要继续抗乙肝病毒治疗, 降低术后肿瘤复发率. 分子靶向药物、免疫治疗在预防原发性肝癌手术切除或肝移植术后肿瘤复发与转移中作用报道较少, 仍需要多中心、大样本的临床研究, 相信随着基础研究和临床工作的不断深入, 筛选有效的分子标志物作为评估预防复发与转移治疗的预测因子, 未来在预防肝癌术后复发与转移中将发挥重要的生物学作用.
转化治疗为部分术前评估不可切除原发性肝癌患者创造了手术切除或肝移植的机会, 而且成功转化并实现手术治疗的肝癌患者与无转化手术切除的患者术后5年生存率(24.9%-57%和30%-60%)相近[48,102]. 但转化治疗仅使8%-18%术前评估不切除肝癌患者成功实现转化接受手术切除[61], 因此根据原发性肝癌患者具体情况, 由放射科、放疗科、病理科、肿瘤内科、肿瘤外科等科室组成多学科诊疗团队(multidisciplinary team, MDT), 制定个体化的联合、序贯转化治疗方案, 以达到最佳的治疗效果. 随着新的化疗药物、分子靶向药物和免疫治疗药物的研制, 以及不同治疗方案的临床实践, 使原发性肝癌转化治疗适应证、方案得到更好的优化, 术后预防肿瘤复发与转移的方案更加完善, 不仅能够显著提高转化治疗后原发性肝癌手术切除或肝移植率, 而且延长患者长期生存期, 改善患者预后, 造福于更多的原发性肝癌患者.
学科分类: 胃肠病学和肝病学
手稿来源地: 上海市
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科学编辑:张砚梁 制作编辑:张砚梁
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