中國(guó)肝癌肝移植臨床實(shí)踐指南

中華醫(yī)學(xué)會(huì)器官移植學(xué)分會(huì)

中華醫(yī)學(xué)會(huì)外科學(xué)分會(huì)移植學(xué)組

中國(guó)醫(yī)師協(xié)會(huì)器官移植醫(yī)師分會(huì)

1 前 言

據(jù)統(tǒng)計(jì)中國(guó)每年超過(guò)30 萬(wàn)人死于肝細(xì)胞肝癌(以下簡(jiǎn)稱(chēng)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(rèn)可的治療終末期肝病最有效的手段之一。我國(guó)自20 世紀(jì)90 年代掀起第二次肝移植熱潮以來(lái)，肝移植事業(yè)發(fā)展迅猛，呈專(zhuān)業(yè)化和規(guī)?；l(fā)展態(tài)勢(shì)，在移植數(shù)量和質(zhì)量方面已接近或達(dá)到西方發(fā)達(dá)國(guó)家水平。截止2014 年4 月，中國(guó)肝移植注冊(cè)網(wǎng)站登記肝移植26 751 例。目前，肝移植在全國(guó)范圍內(nèi)已得到廣泛開(kāi)展，亟待相關(guān)實(shí)踐指南來(lái)指導(dǎo)全國(guó)肝移植工作更規(guī)范、有效、安全地開(kāi)展。中華醫(yī)學(xué)會(huì)器官移植學(xué)分會(huì)、中華醫(yī)學(xué)會(huì)外科學(xué)分會(huì)移植學(xué)組及中國(guó)醫(yī)師協(xié)會(huì)器官移植醫(yī)師分會(huì)組織專(zhuān)家制定肝癌肝移植臨床實(shí)踐指南，重點(diǎn)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(jí)主要參考2001 牛津證據(jù)分級(jí)(詳見(jiàn)表1)，推薦意見(jiàn)強(qiáng)度主要參考GRADE系統(tǒng)推薦分級(jí)等［1-2］。

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(xiàn)是中國(guó)現(xiàn)今拓展供肝來(lái)源的主要方向，而活體肝移植在有豐富移植經(jīng)驗(yàn)的醫(yī)療單位已成為一項(xiàng)成熟技術(shù)［3］。1996 年Mazzaferro 等提出米蘭標(biāo)準(zhǔn)后，符合米蘭標(biāo)準(zhǔn)的肝癌肝移植受者獲得了長(zhǎng)期存活［4-7］。但米蘭標(biāo)準(zhǔn)對(duì)肝癌大小和數(shù)目的限制過(guò)于嚴(yán)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)，中國(guó)大多數(shù)肝癌患者將失去肝移植機(jī)會(huì)。近年來(lái)國(guó)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(University of California，San Francisco，UCSF)標(biāo)準(zhǔn)、Up-to-Seven標(biāo)準(zhǔn)等，這些新標(biāo)準(zhǔn)提出的共同目的是擴(kuò)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(guó)提出的杭州標(biāo)準(zhǔn)是國(guó)際上首個(gè)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(duì)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(shí)，無(wú)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(mǎn)意的術(shù)后生存率［10-15］。近年來(lái)，對(duì)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(zhuān)家主張行搶救性肝移植［16-17］;對(duì)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［17-18］。

表1 循證醫(yī)學(xué)證據(jù)分級(jí)

表2 肝癌肝移植受者選擇標(biāo)準(zhǔn)

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(guò)一系列治療手段，減輕腫瘤負(fù)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(jī)會(huì)。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(wú)門(mén)靜脈主干或下腔靜脈等大血管侵犯、無(wú)遠(yuǎn)處轉(zhuǎn)移的肝癌患者［17，19-21］。降期治療的方法主要有局部消融治療和肝動(dòng)脈栓塞化療(transcatheter hepatic arterial chemoembolization，TACE)等［17，19，22］。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(wú)水乙醇注射等方法。降期治療的療效一般采用對(duì)比增強(qiáng)CT 和MRI，并結(jié)合甲胎蛋白(alpha fetal protein，AFP)水平變化進(jìn)行評(píng)估，評(píng)價(jià)指標(biāo)包括腫瘤大小、數(shù)目和AFP 水平等［22-28］。目前研究認(rèn)為多種治療方法的聯(lián)合應(yīng)用可達(dá)到更好的降期療效［29］。

表3 肝癌肝移植術(shù)前降期治療

4 肝癌肝移植受者抗病毒治療(表4)

中國(guó)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 載量高以及肝移植后乙型肝炎(以下簡(jiǎn)稱(chēng)乙肝)復(fù)發(fā)的受者，肝癌復(fù)發(fā)的風(fēng)險(xiǎn)增加，因此對(duì)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(zhǎng)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(qiáng)效、高耐藥屏障核苷類(lèi)似物(nucleostide analogues，NAs)。移植術(shù)中無(wú)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NAs 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(lái)，研究表明應(yīng)用無(wú)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(bào)道，其臨床應(yīng)用尚有爭(zhēng)議［40-42］。中國(guó)丙型肝炎病毒(hepatitis C virus，HCV)感染患者呈增多趨勢(shì)，HCV RNA 陽(yáng)性患者如肝功能Child-Pugh 評(píng)分≤7，術(shù)前宜進(jìn)行抗病毒治療，移植術(shù)后須經(jīng)病理確認(rèn)丙型肝炎復(fù)發(fā)后方可給予抗HCV 治療［43］。

5 肝癌肝移植受者免疫抑制劑應(yīng)用(表5)

鈣調(diào)磷酸酶抑制劑(calcineurin inhibitor，CNI)的應(yīng)用是肝移植后肝癌復(fù)發(fā)的獨(dú)立危險(xiǎn)因素［44］。對(duì)于肝癌肝移植受者，腫瘤的復(fù)發(fā)風(fēng)險(xiǎn)與其侵襲性及機(jī)體的免疫功能有關(guān)，受者處于強(qiáng)免疫抑制狀態(tài)時(shí)其免疫監(jiān)視系統(tǒng)受到破壞，促進(jìn)腫瘤復(fù)發(fā)、轉(zhuǎn)移，而免疫抑制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(wú)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(gè)體化的低劑量免疫抑制方案［45］。近年來(lái)臨床上有糖皮質(zhì)激素早期撤除、無(wú)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［48-51］。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白介素-2 受體阻滯劑+西羅莫司+嗎替麥考酚酯+糖皮質(zhì)激素;③白介素-2 受體阻滯劑+嗎替麥考酚酯+他克莫司/西羅莫司［52-55］。

表4 肝癌肝移植受者抗病毒治療

表5 肝癌肝移植受者免疫抑制劑應(yīng)用

6 肝癌肝移植術(shù)后復(fù)發(fā)的防治(表6)

文獻(xiàn)報(bào)道，肝癌肝移植術(shù)后5 年肝癌復(fù)發(fā)率可達(dá)20% ～57. 8%，故復(fù)發(fā)轉(zhuǎn)移的防治十分重要［56-57］。肝癌的形態(tài)學(xué)特征(大小、數(shù)目等)、分期、組織學(xué)分級(jí)以及生物學(xué)特性等應(yīng)作為術(shù)后用藥的重要參考，制定個(gè)體化治療方案。

肝癌肝移植術(shù)后可能存在針對(duì)腫瘤的免疫逃逸，故應(yīng)給予受者一定療程的術(shù)后治療，以期盡可能地減少微小轉(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、索拉非尼治療以及系統(tǒng)性化療(如奧沙利鉑或阿霉素分別與氟尿嘧啶聯(lián)合使用)，均可為部分受者提供一定的生存獲益［58-61］。

對(duì)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(zhǎng)受者生存期［17，62-64］。肺轉(zhuǎn)移灶如可切除，首選手術(shù)切除［65］。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［66-68］。此外，有專(zhuān)家提出放療、再次肝移植等可作為治療的選擇。對(duì)于晚期患者，可考慮減少或停止免疫抑制劑的使用。

表6 肝癌肝移植術(shù)后復(fù)發(fā)的防治

編審專(zhuān)家組組長(zhǎng)： 鄭樹(shù)森

編審專(zhuān)家組成員( 按姓氏拼音排序) ： 陳規(guī)劃、陳實(shí)、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(guó)盛、段偉東、傅志仁、高杰、高良輝、何曉順、賀強(qiáng)、景鴻恩、李波、李立、李寧、李玉民、劉景豐、劉軍、盧實(shí)春、呂國(guó)悅、明英姿、彭承宏、彭貴主、彭志海、錢(qián)建民、沈巖、沈中陽(yáng)、石承先、時(shí)軍、孫玉嶺、王偉林、溫浩、吳健、吳忠鈞、夏強(qiáng)、徐驍、嚴(yán)律南、楊廣順、楊家印、楊揚(yáng)、楊占宇、葉啟發(fā)、臧運(yùn)金、張峰、張珉、張水軍、鄭樹(shù)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(qiáng)

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