Philip Chong-hei Kwok   中国香港伊丽莎白医院
　【局部治疗分类及其最新进展】
　　肝细胞肝癌（HCC）的治疗取决于肿瘤的大小、数目、位置及肝功能状况。目前已有多项指南可供临床医生选择合适的治疗方案，例如BCLC指南、日本J-HCC指南和APASL指南。外科手术切除和局部射频消融仅适用于一部分患者，其余肝功能尚好的（Child-Pugh  A/ B级）患者可采用局部治疗，包括肝动脉栓塞化疗（TACE）和肝动脉放疗性栓塞（TARE）。

　　1. 常规TACE（cTACE）
　　使用油性载体（碘油）和化疗药物结合的cTACE正广泛运用。TACE的疗效已在一项多中心、大样本量研究和两项随机对照试验中得到证实，其效果取决于化疗药物的类别及其到达肿瘤组织中的含量。使用微导管的超选择性TACE，则可提高碘油在肿瘤中的含量。Matsui等已证实，碘油溢出至肿瘤旁的门静脉增强了治疗效果。最近，微球囊导管被用于超选择性TACE。传统观念认为肝动脉不应被阻断，相反Irie等却表明了利用球囊导管阻断的超选择性TACE提高了肿瘤中化疗药物的存留，并减少了药物向正常肝组织的分流。

　　2. DEB-TACE
　　TACE存在不良反应，究其原因可能与化疗药物从碘油载体中过早释放、局部肝实质和胆管周围丛的损伤有关。新的研究进展表明，利用其他微球（药物洗脱珠，DEB-TACE）替换碘油可减缓药物的释放速度，并降低全身不良反应的发生率。值得一提的是，这些微球直径为100～300μm，比cTACE形成的栓塞影响更大。然而，Lammer等在一项随机对照试验中发现，尽管DEB-TACE能更好地控制病情发展，但在总体生存方面却并不优于cTACE。DEB-TACE在晚期肝癌患者中的不良反应较少。Malagari等近期发表的研究结果显示，173例接受DEB-TACE 治疗的患者的平均总体生存期为43.8个月，在1、2、3、4和5年整体生存率是93.6%、83.8%、62%、41.04%和22.5%。

　　3. TARE
　　另一项替代性局部治疗是TARE。它应用涂满β-发光钇-90的树脂或玻璃珠，微珠的直径为20～60 μm，可在肿瘤内小动脉的远端驻留。微珠上涂布的每个粒子都具有辐射性，辐射范围是大约2 mm，可发挥近距离放射治疗的作用。几项大型II期临床研究显示，与cTACE相比，TRAE治疗后患者虽然没有明确的生存获益，但TRAE具有较少的副作用、更好的耐受性、更高的应答率、以及更长的至疾病进展时间。而没有明确生存获益的原因可能与治疗对象均为晚期HCC有关。另有一项早期的研究显示，TRAE治疗伴有门静脉癌栓的HCC患者有益。TRAE已成为一些肿瘤治疗中心的门诊治疗项目。

　　【局部治疗与其他方法的联合治疗】
　　上述局部治疗可单独使用，对于适合的患者，也可联合其他治疗方法使用。在治疗意图上，cTACE联合射频消融术已显示出较好的疗效。一项包含6项随机对照研究的荟萃分析显示，与单一治疗相比，联合治疗显示出1年、3年的总体生存期优势（OR值分别为4.61、2.79）以及3年的无复发生存期优势（OR=3.0）

　　目前，针对cTACE 或DEB-TACE在与索拉非尼联合治疗中的作用我们正在进行时效与剂量方面的研究。根据已有数据表明，经TACE治疗1～2天后，血清VEGF水平瞬时增高，30天后又恢复正常。因索拉非尼具有抑制VEGF的作用，所以索拉非尼联合TACE或TARE具有一定的作用。

　　（英文原文）
　　The treatment of hepatocellular carcinoma (HCC) depends on the size， number， location of tumors， and the background liver function. There are different guidelines to help physicians and patients in choosing the appropriate treatmentsuch as the BCLC guidelines， J-HCC guidelines from Japan， and APASL guidelines. Surgical resection and curative loco ablative treatment can only be offered in a limited proportion of patients. For the rest， loco-regional therapy is offered if the liver function remains good (Child’s class A or B). Locoregional therapy includes transarterial chemoembolization (TACE) and transarterial radioembolization (TARE).

　　Conventional transarterial chemoembolization (cTACE) using an emulsion of oily carrier (lipiodol) and chemotherapeutic agent(s) is widely practiced. Its efficacy has been established by multiple large-scale studies and the two randomized controlled trials by Llovet and Lo. The effect of TACE depends on the tumoricidal effect of the chemo mixture and on the amount of lipiodol retention inside the tumor. Super selective TACE using a micro catheter improves the amount of lipiodol retention. It has been proven by Matsui et al that lipiodol overflow (to the portal venules next to the tumor) enhances the treatment effect. Recently， micro balloon catheters were used for super selective TACE. Contrary to the conventional wisdom that the supplying artery should not be blocked or wedged， Irie et al showed that balloon occlusion TACE improves the lipiodol retention inside the tumor and reduces the chemo mixture flowing to the normal liver parenchyma.

　　Side effects of TACE exist and are either related to the early release of chemotherapeutic agents from the oily carrier， or are related to local damage of liver parenchyma and peribiliary plexus. Recent advances include the replacement of the oily carrier with other microspheres (drug eluting beads-TACE/ DEB-TACE). The drugs are released slowly and the incidence of systemic side effects is reduced. The microspheres are smaller (100-300um)， which may create greater embolic effects than cTACE. However， the RCT by Lammer et al (PRECISION V) cannot show an improved survival rate， despite there being better control of disease progression. The side effects of DEB-TACE are less in patients with more advanced disease.  In a recent publication by Malagari et al， the mean overall survival in 173 patients was 43.8 months. The overall survival at 1， 2， 3， 4 and 5 years was 93.6， 83.8， 62， 41.04 and 22.5%.

　　Another alternative is transarterial radioembolization (TARE)， using beta- emitting Yttrium-90 coated on resin or glass beads. The beadsmeasure 20-60 micrometers in size， and are lodged distally in the small arteries inside the tumor. The radiation range of each particle is about 2mm， exerting a local brachytherapy effect. Several large-scale phase II studies show less side effects， better tolerance， better response rate， and longer time to disease progression when compared with cTACE. However， there is no definite survival benefit. This may be related to the use of this treatment in moderate to advanced disease. Early studies show benefit of TARE in HCC with portal vein invasion. TARE is usually given once and some centers perform this as an outpatient procedure.

　　Locoregional treatment may be used alone or in combination with other modes of therapy in suitable patients. For a curative intent， cTACE plus radiofrequency ablation is shown to provide better disease control. In a meta-analysis of 6 RCTs， when compared with monotherapy， combined treatment provides better 1-year and 3-year overall survival(OR= 4.61 and 2.79)and better 3-year recurrence free survival (OR=3.0).

　　The role of cTACE or DEB-TACE in conjunction with sorafenib is being investigated with different timing and dose. It has beenshown that there is a transient increase of plasma VEGF levels after TACE within 1-2 days， and that this becomes normal at 30 days. Sorafenib suppresses VEGF and there may be a role for sorafenib in combination with TACE or TARE.