●指南解讀

中國肝癌肝移植臨床實踐指南中華醫(yī)學(xué)會器官移植學(xué)分會中華醫(yī)學(xué)會外科學(xué)分會移植學(xué)組中國醫(yī)師協(xié)會器官移植醫(yī)師分會

1 前言

據(jù)統(tǒng)計，我國每年超過30萬人死于肝細胞肝癌（以下簡稱肝癌），占全球肝癌死亡人數(shù)的一半左右。而肝移植是被全世界認可的治療終末期肝病最有效的手段之一。我國自20世紀90年代掀起第二次肝移植熱潮以來，肝移植事業(yè)發(fā)展迅猛，呈專業(yè)化和規(guī)?；l(fā)展態(tài)勢，在移植數(shù)量和質(zhì)量方面已接近或達到西方發(fā)達國家水平。截至2014年4月，我國肝移植注冊網(wǎng)站登記肝移植26751例。目前，肝移植在全國范圍內(nèi)已得到廣泛開展，亟待相關(guān)實踐指南來指導(dǎo)全國肝移植工作更規(guī)范、有效、安全地開展。中華醫(yī)學(xué)會器官移植學(xué)分會、中華醫(yī)學(xué)會外科學(xué)分會移植學(xué)組及中國醫(yī)師協(xié)會器官移植醫(yī)師分會組織專家制定肝癌肝移植臨床實踐指南，重點闡述肝移植受者選擇標(biāo)準(zhǔn)、術(shù)前降期治療、抗病毒治療、免疫抑制劑應(yīng)用、術(shù)后復(fù)發(fā)防治五部分內(nèi)容。本指南采用的循證醫(yī)學(xué)證據(jù)分級主要參考2001牛津證據(jù)分級（表1），推薦意見強度主要參考證據(jù)推薦分級的評估、制定與評價（GRADE）系統(tǒng)推薦分級等[1-2]。

表1 循證醫(yī)學(xué)證據(jù)分級

2 肝癌肝移植受者選擇標(biāo)準(zhǔn)（表2）

供肝短缺是世界性難題，故應(yīng)將寶貴的供肝資源優(yōu)先分配給肝移植的最大獲益者。心臟死亡器官捐獻是中國現(xiàn)今拓展供肝來源的主要方向，而活體肝移植在有豐富移植經(jīng)驗的醫(yī)療單位已成為一項成熟技術(shù)[3]。1996年Mazzaferro等[4]提出米蘭標(biāo)準(zhǔn)后，符合米蘭標(biāo)準(zhǔn)的肝癌肝移植受者獲得了長期存活[5-7]，但米蘭標(biāo)準(zhǔn)對肝癌大小和數(shù)目的限制過于嚴格，更重要的是忽略了腫瘤的生物學(xué)特性。如果根據(jù)米蘭標(biāo)準(zhǔn)，我國大多數(shù)肝癌患者將失去肝移植機會。近年來國際上涌現(xiàn)出一些新的肝癌肝移植受者選擇標(biāo)準(zhǔn)，如加州大學(xué)洛杉磯分校（UCSF）標(biāo)準(zhǔn)、Upto-Seven標(biāo)準(zhǔn)等，提出這些新標(biāo)準(zhǔn)的共同目的是擴大受者人群并取得與米蘭標(biāo)準(zhǔn)相似的移植生存率[8-9]。2008年，中國提出的杭州標(biāo)準(zhǔn)是國際上率先引入腫瘤生物學(xué)特性和病理學(xué)特征的移植標(biāo)準(zhǔn)，這是對以往標(biāo)準(zhǔn)局限于腫瘤形態(tài)學(xué)的巨大突破。研究證實，無論是尸體肝移植還是活體肝移植，符合杭州標(biāo)準(zhǔn)的肝癌受者均獲得滿意的術(shù)后生存率[10-15]。近年來，對于肝癌切除術(shù)后復(fù)發(fā)者，如符合肝移植準(zhǔn)入標(biāo)準(zhǔn)，多數(shù)專家主張行搶救性肝移植；對于肝癌肝移植術(shù)后移植物失功者，再次肝移植應(yīng)審慎考慮[16-17]。

3 肝癌肝移植術(shù)前降期治療（表3）

肝癌肝移植術(shù)前腫瘤降期治療是通過一系列治療手段，減輕腫瘤負荷，降低分期，使超出肝癌肝移植受者選擇標(biāo)準(zhǔn)的患者能夠被納入移植標(biāo)準(zhǔn)，獲得肝移植機會。降期治療主要適用于不符合現(xiàn)有肝癌肝移植標(biāo)準(zhǔn)，且無門靜脈主干或下腔靜脈等大血管侵犯、無遠處轉(zhuǎn)移的肝癌患者[18-21]。降期治療的方法主要有局部消融治療和肝動脈栓塞化療（transcatheter hepatic arterial chemoembolization，TACE）等[18-19，22]。局部消融治療包括射頻消融、微波消融、冷凍消融和經(jīng)皮無水乙醇注射等方法。降期治療的療效一般采用對比增強CT和MRI，并結(jié)合甲胎蛋白（alpha fetal protein，AFP）水平變化進行評估，評價指標(biāo)包括腫瘤大小、數(shù)目和AFP水平等心[22-28]。目前研究認為，多種治療方法的聯(lián)合應(yīng)用可達到更好的降期療效[29]。

表2 肝癌肝移植受者選擇標(biāo)準(zhǔn)建議

表3 肝癌肝移植術(shù)前降期治療建議

4 肝癌肝移植受者抗病毒治療（表4）

中國肝癌肝移植受者90%以上與乙型肝炎病毒（hepatitis B virus，HBV）感染相關(guān)。肝移植前HBV載量高及肝移植后乙型肝炎（簡稱乙肝）復(fù)發(fā)的受者，肝癌復(fù)發(fā)的風(fēng)險增加，因此，對乙肝肝移植受者盡早行抗病毒治療，盡快降低HBV水平，有助于降低移植術(shù)后乙肝復(fù)發(fā)率，提高受者長期生存率[30-32]。HBV載量高的等待肝移植患者應(yīng)采用恩替卡韋等強效、高耐藥屏障核苷類似物（nucleosideanalogue，NA）。移植術(shù)中無肝期應(yīng)給予乙型肝炎免疫球蛋白（hepatitis B immunoglobulin，HBIG）。移植后的主要抗病毒治療方案為NA聯(lián)合低劑量HBIG，其中恩替卡韋或替諾福韋的聯(lián)合方案能更好地預(yù)防移植術(shù)后乙肝復(fù)發(fā)[33-38]。近年來，研究表明應(yīng)用無激素免疫抑制方案可降低移植術(shù)后乙肝復(fù)發(fā)率[39]。此外也有移植術(shù)后接種乙肝疫苗預(yù)防乙肝復(fù)發(fā)的報道，其臨床應(yīng)用尚有爭議[40-42]。中國丙型肝炎病毒（hepatitis C virus，HCV）感染患者呈增多趨勢，HCV RNA陽性患者如肝功能Child-Pugh評分≤7，術(shù)前宜進行抗病毒治療，移植術(shù)后需經(jīng)病理確認丙型肝炎復(fù)發(fā)后方可給予抗HCV治療[43]。

表4 肝癌肝移植受者抗病毒治療建議

5 肝癌肝移植受者免疫抑制劑應(yīng)用（表5）

應(yīng)用鈣調(diào)磷酸酶抑制劑是肝移植后肝癌復(fù)發(fā)的獨立危險因素[44]。對于肝癌肝移植受者，腫瘤的復(fù)發(fā)風(fēng)險與其侵襲性及機體的免疫功能有關(guān)，受者處于強免疫抑制狀態(tài)時其免疫監(jiān)視系統(tǒng)受到破壞，促進腫瘤復(fù)發(fā)、轉(zhuǎn)移，而免疫抑制劑的劑量不足則容易誘發(fā)排斥反應(yīng)。如何維持這一平衡，目前尚無定論[45-47]。肝癌肝移植受者目前尚不建議免疫抑制劑的全線撤除，但主張個體化的低劑量免疫抑制方案[45]。近年來臨床上有糖皮質(zhì)激素早期撤除、無糖皮質(zhì)激素及使用具有腫瘤抑制作用的mTOR抑制劑（西羅莫司為代表）的成功應(yīng)用方案Ⅲ[48-50]。目前臨床上主要的免疫抑制方案為：（1）他克莫司或環(huán)孢素+嗎替麥考酚酯+糖皮質(zhì)激素；（2）IL-2受體阻滯劑+西羅莫司+嗎替麥考酚酯+糖皮質(zhì)激素；（3）IL-2受體阻滯劑+嗎替麥考酚酯+他克莫司/西羅莫司[51-54]。

6 肝癌肝移植術(shù)后復(fù)發(fā)的防治（表6）

文獻報道，肝癌肝移植術(shù)后5年肝癌復(fù)發(fā)率可達20.0%～57.8%，故復(fù)發(fā)轉(zhuǎn)移的防治十分重要[9，55]。肝癌的形態(tài)學(xué)特征（大小、數(shù)目等）、分期、組織學(xué)分級及生物學(xué)特性等應(yīng)作為術(shù)后用藥的重要參考，制定個體化治療方案。

表5 肝癌肝移植受者免疫抑制劑應(yīng)用建議

肝癌肝移植術(shù)后可能存在針對腫瘤的免疫逃逸，故應(yīng)給予受者一定療程的術(shù)后治療，以期盡可能她減少微小轉(zhuǎn)移灶，降低術(shù)后復(fù)發(fā)率。選用碘131美妥昔單抗放射免疫治療、索拉非尼治療及系統(tǒng)性化療（如奧沙利鉑或阿霉素與氟尿嘧啶聯(lián)合使用），均可為部分受者提供一定的生存獲益[56-59]。

對于肝移植術(shù)后肝癌復(fù)發(fā)轉(zhuǎn)移者，應(yīng)用索拉非尼治療可延長受者生存期[18，60-62]。肺轉(zhuǎn)移灶如可切除，首選手術(shù)切除[63]。移植肝內(nèi)復(fù)發(fā)病灶的局部治療包括手術(shù)切除、TACE、局部消融等[64-66]。此外，有專家提出放療、再次肝移植等可作為治療的選擇。對于晚期患者，可考慮減少或停止免疫抑制劑的使用。

編審專家組組長：鄭樹森

編審專家組成員（按姓氏拼音排序）：陳規(guī)劃、陳實、陳孝平、陳燕凌、陳知水、陳忠華、丁義濤、董家鴻、竇劍、竇科峰、杜國盛、段偉東、傅志仁、高杰、高良輝、何曉順、賀強、景鴻恩、李波、李立、李寧、李玉民、劉景豐、劉軍、盧實春、呂國悅、明英姿、彭承宏、彭貴主、彭志海、錢建民、沈巖、沈中陽、石承先、時軍、孫軍輝、孫玉嶺、王偉林、溫浩、吳健、吳忠鈞、夏強、徐驍、嚴律南、楊廣順、楊家印、楊揚、楊占宇、葉殷發(fā)、臧運金、張峰、張珉、張水軍、鄭樹森、周琳、朱繼業(yè)、朱志軍

執(zhí)筆：徐驍、李建輝、高峰、陳峻、舒哲悅、方維佳、衛(wèi)強

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（本文轉(zhuǎn)載自《中華外科雜志》2014年10月第52卷第10期）

10.3760/cma.j.issn.0529-5815.2014.10.001

310003 杭州，浙江大學(xué)醫(yī)學(xué)院附屬第一醫(yī)院肝膽胰外科衛(wèi)生部多器官聯(lián)合移植研究重點實驗室

鄭樹森，Email：zyzss@ZJU.edu.cn