修回日期: 2003-01-10
接受日期: 2003-02-12
在线出版日期: 2003-03-15
本文简述2000年以来国外文献和复旦大学肝癌研究所的部分工作. 小肝癌切除的疗效继续得到公认, 局部治疗的疗效虽未超过切除, 但未来将部分取代切除. 微创外科和微创外科观念值得重视. 肝癌筛查可使更多患者获得治疗机会. 肝癌切除的禁区已基本攻克, 未来将更多研究对合并肝内静脉癌栓的外科综合治疗. 临床肝癌中不能切除者仍将占多数, 由于局部治疗的进步, 不能切除肝癌的降期后(缩小后)切除是部分不能切除肝癌的一条出路. 对于小肝癌, 肝移植的无瘤生存率高于切除者, 故其作用将缓慢上升. 21世纪肝癌转移复发的研究将成为重点, 目前在转移复发预测和预防方面已有不少进展, 但成为临床常规还有待时日. 随机分组试验和荟萃分析是推动肝癌外科进步的必由之路.
引文著录: 汤钊猷. 肝癌外科治疗的进展. 世界华人消化杂志 2003; 11(3): 249-254
Revised: January 10, 2003
Accepted: February 12, 2003
Published online: March 15, 2003
N/A
- Citation: N/A. N/A. Shijie Huaren Xiaohua Zazhi 2003; 11(3): 249-254
- URL: https://www.wjgnet.com/1009-3079/full/v11/i3/249.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v11.i3.249
笔者不久前才发表过"肝癌病因、治疗和转移"的综述(World J Gastroenterol 2001; 7: 445-454), 故本文仅列述2000年以来的主要国外文献和复旦大学肝癌研究所(以下简称我所)的部分工作.
即使在21世纪, 小肝癌的外科治疗仍将起重要作用, 为此肝癌筛查问题仍无法回避. McMahon et al[1]通过16年对阿拉斯加土著乙肝携带者的筛查, 认为每半年一次的AFP检测可查出仍可切除的肝癌, 并明显提高生存率. 香港认为, 早期发现可使更多的肝癌患者获得治疗的机会[2]. 意大利的结果提示, 对肝硬化患者每年或每半年监测, 可使更多肝癌患者获得局部治疗、化疗栓塞或肝移植的机会, 从而延长生存期[3]. 我国台湾对乙型肝炎高发区的肝癌高危人群进行超声显像筛查, 并与未筛查组对比, 死亡率降低41%[4]. 我所对肝癌高危人群进行前瞻性随机分组筛查试验(筛查组9 373人, 未筛查组9 443人), 使用检测血中AFP和超声显像的方法每6 mo进行一次筛查提示, 与未筛查组相比, 小肝癌比例为45.3% vs 0, 切除率为46.5% vs 7.5%, 5年生存率为46.4% vs 0, 肝癌死亡率为83.2/10万vs 131.5/10万[5].
小肝癌切除的效果已得到公认. 我所对比小肝癌(1 000例)和大肝癌(1 366例)切除, 5年生存率为62.7% vs 37.1%[6]. Hanazaki et al[7]253例小肝癌切除的5年生存率为47%, 133例≥5 cm肝癌切除则为28%. 我所对小肝癌进行的分子生物学研究表明, 与癌细胞侵袭性相关的分子指标, 在小肝癌的表达仅略低于大肝癌, 提示即使是小肝癌, 进一步提高疗效的关键仍然是癌细胞的生物学特性(Tang et al1998).
近年局部治疗兴起, 局部治疗实际上是外科治疗的延伸. 小肝癌的局部治疗能否取代切除, 不妨列述一下各种局部治疗对小肝癌的疗效, 让读者自行判断. (1)射频消融(RFA)-Livraghi et al[8]报告对肝癌进行射频治疗, 病灶完全坏死的比例与肿瘤大小有关, <3 cm者达90%, 3-5 cm者71%, 5.1-9 cm者45%; Child A单个肝癌<5 cm的3年生存率为85%. Buscarini et al[9] 88例小肝癌射频治疗5年生存率为33%, 但5 a无瘤生存率仅3%. (2)经皮乙醇注射(PEI)-Yamamoto et al[10]观察到小肝癌切除与经皮乙醇注射(PEI)的5年累计生存率相仿(61.5% vs 59.0%), 但5年无瘤生存率则切除者较高(25.7% vs 9.7%). 对111例Child A肝硬化小肝癌的PEI治疗, 5年生存率为41%[11]. (3)经皮微波治疗(PMCT)－Lu et al[12] 50例平均直径2.7 cm小肝癌PMCT治疗后3年生存率为73%. Itamoto et al[13] 33例小肝癌PMCT治疗后5年生存率为48.6%. (4)激光热消融(LTA)-Pacella et al[14] 15例小肝癌激光热消融合并TACE治疗后5年生存率为40%. 总体而言, 局部治疗的远期疗效似仍未超过切除, 但患者情况不完全相同, 需进行随机分组试验和荟萃分析才能获得结论.
大肝癌规范的外科治疗已有半个世纪的历史, 肝内几乎任何部位肿瘤的切除, 在技术上都已解决, 故突破性进展不多. Poon et al[15]认为切沿宽度并不影响复发率, 因多数肝内复发来自静脉播散. 肝尾叶切除报道日多, 我所12例尾叶切除的5年生存率为37.8%[16]. 近年对合并门静脉癌栓者采取积极外科治疗逐渐增多, 我所分析: 肝癌切除＋癌栓摘除＋术后血管内化疗, 肝癌切除＋癌栓摘除, 肝动脉结扎和/或插管和保守治疗4组的5年生存率依次为26.8%, 16.6%, 0%和0%[17]. Fukuda et al[18]19例合并门静脉主干、下腔静脉或肝外胆管癌栓者作切除和癌栓摘除, 3年生存率为48.5%. 关于围手术期输血, 亦有人认为并不影响切除后的无瘤生存率[19]. Wakabayashi et al[20]认为较大肝癌术前应用门静脉支栓塞(PVE)可能有助提高切除率, 但并不改善预后.
这是近20年发展起来的值得重视的途径, 我所在1980年代起曾有不少报道. 2001年Lau et al[21]报告150例不能切除肝癌全身化疗(顺铂＋阿霉素＋5-Fu)合并α干扰素, 结果15例获序贯切除, 其3年生存率为53%. 近年局部治疗和适形放疗有所开展, 加上与TACE的合并应用, 增加了使肿瘤缩小的途径. 我所曾报告65例不能切除肝癌经TACE治疗肿瘤缩小后切除, 其5年生存率为56%(Fan et al1998). 根据最新材料, 我所90例手术证实≥8 cm (中位直径12 cm, 合并肝硬化81.8%)不能切除肝癌缩小后切除的5年生存率为53.2%, 这90例患者中85.6%采用了肝动脉结扎、肝动脉插管化疗、导向治疗/外放射治疗中的三联或二联治疗作为缩小疗法.
有报道在腹腔镜下行30例肝切除, 但主要是左肝或右肝边缘可作局部切除的病灶[22]. Shimada et al[23]比较17例肝癌腹腔镜手术和38例肝癌开腹手术, 无论手术时间、失血量、术后并发症和生存率均无明显差别, 而前者住院时间明显缩短, 但患者需严格挑选. Biertho et al[24]汇总文献168例腹腔镜肝切除术(其中102例为恶性肿瘤), 并发症率16.1% (包括气栓), 死亡率0.54%. 在腹腔镜下行局部治疗的报道则较多, 如微波固化[25], 乙醇注射[26], 射频治疗[27], 放置肝动脉灌注泵[28]等. 但Ishida et al[29]在鼠实验发现腹腔充气压力可促使癌转移.
Figueras et al[30]比较85例肝移植和35例手术切除, 5年生存率为60% vs 51%, 5年无瘤生存率为60% vs 31%, 血管侵犯为主要预后因素. Hemming et al[31]112例非纤维板层型肝癌作肝移植, 5年生存率为57%, 乙肝相关肝癌较非乙肝相关者差(43% vs 64%), 但用抗病毒治疗后提高到77%; 有血管侵犯者明显差于无血管侵犯者(4% vs 65%). 关于肝癌行肝移植的指征, Figueras et al[32]认为适合于AFP较低、无明显血管侵犯或肝外转移的小肝癌. Margarit et al[33]103例伴肝硬化小肝癌(平均肿瘤大小3.1 cm, 多个结节59%, 累及左右肝31%, 血管侵犯9.2%)行肝移植, 5年生存率为58%, 与因肝硬化行肝移植者相仿(63%), 亦认为肝移植适于伴肝硬化的小肝癌. Yao et al[34]根据70例伴肝硬化肝癌行肝移植的结果, 认为单个肿瘤≤6.5 cm, 或≤3个结节其最大肿瘤≤4.5 cm以及肿瘤总直径≤8 cm者, 其5年生存率仍达75.2%, 从而认为肝移植指征中肿瘤大小可适当放宽. 对合并肝硬化的不能切除小肝癌行肝移植, 采用活体供肝, 因避免等待供肝而优于尸体肝, 明显延长预期寿命[35,36]. 对略大的肝癌(5-7 cm), 如能合并综合治疗(TACE、化疗), 其效果亦可, 而>7 cm者则效果差[37]. TNM第IV期肝癌则不适合行肝移植[38]. 肝移植后同样有乙型肝炎感染复发, 亚裔患者的预后比白人差[39].
无论一期或二期切除, 无论肝癌切除或肝移植, 所遇到的最重要问题乃转移复发. 研究转移复发有两大目标, 一是有效的预测, 二是有效的预防. 较早报道的预测指标, 除临床和病理指标外, 主要是细胞水平的指标, 如: PCNA(增生细胞核抗原)、AFP mRNA、AFP-L3、DNA倍体、雄激素/雌激素受体等. 近年多集中在分子指标方面. (1)细胞增生、运动和凋亡相关指标, 如p53突变和P53抗体、MDM-2[40]、p73、p27[41,42]、c-myc、Ki-67、Kai-1、Rb蛋白、HGF、端粒酶[43]、IL-10[44]等. (2)细胞黏附和细胞外基质降解相关指标, 如上皮细胞钙粘蛋白(E-cadherin)、整合素(Integrin b1)、beta-Catenin[45]、细胞间黏附分子-1(ICAM-1)、CD44[46]、细胞黏附调节分子(CMAR)、基质金属蛋白酶(MMP-9)、人巨噬细胞金属弹性蛋白酶(HME)[47]、TIMP-1(组织金属蛋白酶抑制剂－1)、uPA(尿激酶型纤溶酶原激活物)、骨连接素(osteonectin, ON/SPARC)、Syndecan-1等. (3)血管生成相关指标, 如VEGF(血管内皮细胞生长因子)[48]、PD-ECGF(血小板衍化内皮细胞生长因子)、微血管密度(MVD)等. (4)免疫相关指标, 如淋巴细胞浸润、术前自然杀伤细胞(NK)活性等. 在上述指标中, 能够在血中测出者更有潜在应用价值. Ijichi et al[49]前瞻性研究表明术后血中AFP mRNA的阳性率有助预测复发. 但亦有人持否定意见[50]. Charuruks et al[51]认为检测血清中P53蛋白和P53抗体是有用的预后指标. Poon et al[52]报道术前血清碱性成纤维细胞生长因子(bFGF)水平高, 术后常早期复发. Kobayashi et al[43]认为端粒酶活性是独立的复发预测指标. Mou et al[53]认为随访血中MAGE-1和MAGE-3可早期预测复发. 然而Parasole et al[54]认为血清中sICAM-1、sIL-2R、IL-6和抗P53均无预测价值.
我所就血中的相关指标也作了探索, 观察到: (1)血中血栓调节蛋白(Thrombomodulin, ELISA法)与门脉癌栓形成和肝内播散呈负相关[55]. (2)血中ICAM-1(intercellular adhesion molecule-1, 细胞间黏附分子-1)与肝癌侵袭性呈正相关, 转移组高于非转移组[56]. (3)血中PAI-1 (尿激酶型纤溶酶原激活物受体的抑制剂)水平与肝癌侵袭性呈正相关. 侵袭性肝癌和非侵袭性肝癌比, 血浆中PAI-1水平明显较高[57]. (4)血清基质金属蛋白酶-2(MMP-2)与肝细胞癌根治性切除术后转移复发有关[58]. (5)血中VEGF水平与肝癌侵袭转移呈正相关[59,60]. (6)碱性成纤维细胞生长因子(bFGF)是预测肝细胞癌患者术后转移复发的潜在指标[61]. (7)高转移倾向组患者血浆DNA中D14S62和D14S51(14q染色体)杂合性丢失(LOH)的阳性率低[62].
在手术切除标本的免疫组化检测方面, 观察到: (1)有p53或p16突变者复发率高、生存率低[63,64]. 最近发现p53免疫组化的积分与肝癌预后的相关性好[65]. (2)转化生长因子α(TGFα)可诱导细胞增生和表皮生长因子受体(EGF-R)的表达, 而EGF-R的表达与预后差有关[66,67]. (3)转移抑制基因nm23-H1或Kai-1的表达则与肝癌的侵袭性呈负相关[68-70]. (4)凡MMP-2在癌的表达高于癌周肝者预后差[71]. (5) uPA的表达也与癌侵袭性呈正相关[72]. (6)ICAM-1在癌组织的表达也和肝癌侵袭性呈正相关, 转移组高于非转移组[73]. (7)VEGF和/或PD-ECGF的表达与肝癌侵袭性呈正相关[74,75]. (8)小肝癌微血管密度(MVD)高者预后差, 少血管型小肝癌的5年无瘤生存率高于多血管型者, 分别为74.6%和34.7%[76].
我所在1980年代即已报道对亚临床期复发的再切除可明显延长生存期, 其后也一再证明这个论点(Tang et al1984, Zhou et al1993, Zhou et al1994). 目前, 认为复发行再切除的疗效最好已得到公认. Sugimachi et al[77] 78例复发再切除的5年生存率为47.5%. Arii et al[78]28例再切除, 5年生存率自初次手术算起为62%, 自再切除算起为47%. Matsuda et al[79]认为复发来自多中心发生者的再手术(切除或微波)预后优于复发来自肝内转移者, 5年生存率分别为58.1%和14.3%. 关于术后肾上腺转移, 多主张手术切除[80].
过去文献对可切除肝癌的术前TACE多持否定态度, 认为推迟了患者的手术时间, 因TACE影响肝功能而增加手术风险, 因TACE后粘连多而增加手术难度, 且远期生存率还有所下降. 但对仍局限的不能切除肝癌, TACE是使肿瘤缩小的有效方法. 近年Gerunda et al[81]对比术前TACE组和对照组, 总生存率相仿, 而无瘤生存率则TACE组较好. Yoshida et al[82]报告术前经导管免疫栓塞(OK-432＋纤维蛋白原＋凝血酶)比TACE好.
关于术后预防转移复发: (1)术后TACE－Shimoda et al回顾性分析认为术后TACE (阿霉素＋碘油)与对照组相比, 5年无瘤生存率为31.1% vs 7.9%[83]. (2)术后肝血管内化疗－过去虽有报告认为有用, 但前瞻性随机分组试验认为无效(Ono et al, 1997). (3)术后全身化疗－过去前瞻性随机分组试验认为术后给予表阿霉素与HCFU并不优于对照组(Ono et al, 1997). 另一随机分组试验, 术后静脉表阿霉素合并肝动脉内化疗碘油, 不仅预后更差, 且肝外复发也多(Lai et al, 1998). 但Huang et al[84]前瞻性研究提示术后静脉应用表阿霉素和丝裂霉素有减少复发和改善预后的倾向. Ono et al[85]对三个随机分组试验作荟萃分析(meta-analysis)提示, 在伴有肝硬化的患者肝癌切除后给予化疗, 反而增加余肝的复发, 且远期疗效更差. (4)干扰素术后预防复发－Ikeda et al[86]认为β干扰素对丙型肝炎相关肝癌切除或乙醇注射后的复发有预防作用, 中位随访25 mo时, 与对照组比, 复发为1/10 vs 7/10. Kubo et al[87]随机分组试验证实, α干扰素可减少丙型肝炎相关肝癌切除后的复发, 与对照组相比复发为5/15 vs 12/15.Suou et al[88]也有类似报道. (5)放射性碘标碘油(131I-Lipiodol)-随机分组试验表明, 肝动脉内一次注射131I-Lipiodol 1 850 MBq可减少术后复发(Lau et al, 1999). Partensky et al[89]报道131-Lipiodol作为肝癌根治性切除后辅助治疗的II期临床试验亦获得类似结果. (6)维甲酸类药物－1996年Muto et al曾报道术后口服Polyprenoic acid (维甲酸类)可减少术后复发, 1999年再次报道远期结果, 6年生存率治疗组为74%, 而对照组为46%. (7)过继免疫治疗-Takayama et al随机分组试验表明, 76例接受370次淋巴细胞输注, 平均随访4.4年, 与对照组比, 复发率为59% vs 77%[89].
总之, 在过去100年的肝癌治疗历史上, 外科治疗始终占有最重要的地位. 预期在21世纪, 肝癌外科仍将占重要地位, 但肝癌治疗的模式和重点将有所改变. (1)小肝癌切除仍将有其位置, 但有一部分将被局部治疗所取代; 腹腔镜下的小肝癌切除或局部治疗将明显增加; 癌细胞生物学特性的研究将成为重点. (2)肝癌切除的禁区在20世纪已基本攻克, 21世纪将更多研究对合并肝内静脉癌栓的外科综合治疗. (3)由于不能切除肝癌仍将占临床肝癌的大多数, 加上局部治疗的兴起, 以及多数局部治疗的不彻底性, 不能切除肝癌的降期后切除(或缩小后切除)仍将是部分不能切除肝癌的一条重要出路. (4)微创外科以及微创外科观念将受到更多的关注. (5)肝移植在肝癌治疗中的地位将缓慢上升, 一些瓶颈问题仍待解决. (6) 术后转移复发的研究将成为肝癌外科研究的重点, 生物治疗的进步, 可能给转移复发的预防提供新的途径. 随机分组试验和荟萃分析将成为推动肝癌临床进步的必由之路.
编辑: N/A
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