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)中國每年超過30 萬人死于肝細(xì)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(rèn)可的治療終末期肝病最有效的手段之一。我國自20 世紀(jì)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(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)國家水平。截止2014 年4 月，中國肝移植注冊(cè)網(wǎng)站登記肝移植26 751 例。目前，肝移植在全國范圍內(nèi)已得到廣泛開展，亟待相關(guān)實(shí)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(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)組及中國醫(yī)師協(xié)會(huì)器官移植醫(yī)師分會(huì)組織專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)(詳見表1)，推薦意見強(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(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)，中國大多數(shù)肝癌患者將失去肝移植機(jī)會(huì)。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(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，中國提出的杭州標(biāo)準(zhǔn)是國際上首個(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(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)，且無門靜脈主干或下腔靜脈等大血管侵犯、無遠(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(以下簡稱乙肝)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、高耐藥屏障核苷類似物(nucleostide analogues，NAs)。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，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(bào)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(shì)，HCV RNA 陽性患者如肝功能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［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(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(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)

1 Oxford Centre for Evidence-based Medicine—Levels of Evidence(March 2009)［DB/OL］. Oxford Centre for Evidence-based Medicine，2009［2014-04-15］. http://www. cebm. net/oxfordcentre-evidence-based-medicine-levels-evidence-march-2009/.

2 Schünemann HJ，Oxman AD，Brozek J，et al. Grading quality of evidence and strength of recommendations for diagnostic tests and strategies［J］. BMJ，2008，336(7653):1106-1110.

3 Liang WH，Wu LW，Ling XT，et al. Living donor liver transplantation versus deceased donor liver transplantation for hepatocellular carcinoma:a meta-analysis［J］. Liver Transpl，2012，18(10):1226-1236.

4 Mazzaferro V，Regalia E，Doci R，et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis［J］. N Engl J Med，1996，334(11):693-699.

5 European Liver Transplant Registry Results［DB/OL］. European Liver Transplant Registry，2011［2014-04-15］. http://www.eltr.org.

6 OPTN/SRTR Annual Report［DB/OL］. Organ Procurement and Transplantation Network，2011［2014-04-15］. http://www.ustransplant.org.

7 Mazzaferro V，Bhoori S，Sposito C，et al. Milan criteria in liver transplantation for hepatocellular carcinoma: an evidence-based analysis of 15 years of experience［J］. Liver Transpl，2011，17(Suppl 2):S44-S57.

8 Yao FY，F(xiàn)errell L，Bass NM，et al. Liver transplantation for hepatocellular carcinoma:expansion of the tumor size limits does not adversely impact survival［J］.Hepatology，2001，33(6):1394-1403.

9 Mazzaferro V，Llovet JM，Miceli R，et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria:a retrospective，exploratory analysis［J］. Lancet Oncol，2009，10(1):35-43.

10 Zheng SS，Xu X，Wu J，et al. Liver transplantation for hepatocellular carcinoma:Hangzhou experiences［J］. Transplantation，2008，85(12):1726-1732.

11 Lei JY， Wang WT， Yan LN. Hangzhou criteria for liver transplantation in hepatocellular carcinoma: a single-center experience［J］. Eur J Gastroenterol Hepatol，2014，26(2):200-204.

12 Audet M，Panaro F，Piardi T，et al. Are the Hangzhou criteria adaptable to hepatocellular carcinoma patients for liver transplantation in Western countries?［J］. Liver Transpl，2009，15(7):822-823.

13 Chen J，Xu X，Wu J，et al. The stratifying value of hangzhou criteria in liver transplantation for hepatocellular carcinoma［J］. PLoS One，2014，9(3):e93128.

14 徐驍，楊家印，鐘林，等. 肝癌肝移植“杭州標(biāo)準(zhǔn)”多中心應(yīng)用研究——1163 例報(bào)道［J］. 中華器官移植雜志，2013，34(9):524-527.

15 鄭樹森，汪愷，徐驍，等. 肝移植治療肝癌的受者選擇杭州標(biāo)準(zhǔn)在親屬活體供肝移植中的應(yīng)用價(jià)值［J］. 中華器官移植雜志，2011，32(6):330-333.

16 Hu ZH，Wang W，Li ZW，et al. Recipient outcomes of salvage liver transplantation versus primary liver transplantation:a systematic review and meta-analysis［J］. Liver Transpl，2012，18(11):1316-1323.

17 Clavien PA，Lesurtel M，Bossuyt PM，et al. Recommendations for liver transplantation for hepatocellular carcinoma:an international consensus conference report［J］. Lancet Oncol，2012，13(1):e11-e22.

18 Olthoff KM，Merion RM，Ghobrial RM，et al. Outcomes of 385 adult-to-adult living donor liver transplant recipients:a report from the A2ALL Consortium［J］. Ann Surg，2005，242(3):314-323.

19 Galuppo R，McCall A，Gedaly R. The role of bridging therapy in hepatocellular carcinoma［J］. Int J Hepatol，2013:419302.

20 European Association for the Study of the Liver. EASL-EORTC clinical practice guidelines:management of hepatocellular carcinoma［J］. J Hepatol，2012，56(4):908-943.

21 Washburn K，Edwards E，Harper A，et al. Hepatocellular carcinoma patients are advantaged in the current liver transplant allocation system［J］. Am J Transplant，2010，10(7):1643-1648.

22 Lewandowski RJ，Kulik LM，Riaz A，et al. A comparative analysis of transarterial downstaging for hepatocellular carcinoma:chemoembolization versus radioembolization［J］. Am J Transplant，2009，9(8):1920-1928.

23 Merani S，Majno P，Kneteman NM，et al. The impact of waiting list α-fetoprotein changes on the outcome of liver transplant for hepatocellular carcinoma［J］. J Hepatol，2011，55(4):814-819.

24 Mailey B，Artinyan A，Khalili J，et al. Evaluation of absolute serum α-fetoprotein levels in liver transplant for hepatocellular cancer［J］.Arch Surg，2011，146(1):26-33.

25 Ravaioli M，Grazi GL，Piscaglia F，et al. Liver transplantation for hepatocellular carcinoma:results of down-staging in patients initially outside the Milan selection criteria［J］. Am J Transplant，2008，8(12):2547-2557.

26 Yao FY，Kerlan RK Jr，Hirose R，et al. Excellent outcome following down-staging of hepatocellular carcinoma prior to liver transplantation:an intention-to-treat analysis［J］. Hepatology，2008，48(3):819-827.

27 Duvoux C， Roudot-Thoraval F， Decaens T， et al. Liver transplantation for hepatocellular carcinoma:a model including αfetoprotein improves the performance of Milan criteria ［J］.Gastroenterology，2012，143(4):986-994.

28 Lai Q，Avolio AW，Graziadei I，et al. Alpha-fetoprotein and modified response evaluation criteria in solid tumors progression after locoregional therapy as predictors of hepatocellular cancer recurrence and death after transplantation［J］. Liver Transpl，2013，19(10):1108-1118.

29 Ashoori N，Bamberg F，Paprottka P，et al. Multimodality treatment for early-stage hepatocellular carcinoma:a bridging therapy for liver transplantation［J］. Digestion，2012，86(4):338-348.

30 Koda M，Nagahara T，Matono T，et al. Nucleotide analogs for patients with HBV-related hepatocellular carcinoma increase the survival rate through improved liver function［J］. Inter Med，2009，48(1):11-17.

31 Wong JS，Wong GL，Tsoi KK，et al. Meta-analysis:the efficacy of anti-viral therapy in prevention of recurrence after curative treatment of chronic hepatitis B-related hepatocellular carcinoma［J］. Aliment Pharmacol Ther，2011，33(10):1104-1112.

32 Wu JC，Huang YH，Chau GY，et al. Risk factors for early and late recurrence in hepatitis B-related hepatocellular carcinoma［J］. J Hepatol，2009，51(5):890-897.

33 European Association for the Study of the Liver. EASL clinical practice guidelines:Management of chronic hepatitis B virus infection［J］. J Hepatol，2012，57(1):167-185.

34 Chen CJ，Yang HI，Iloeje UH;REVEAL-HBV Study Group.Hepatitis B virus DNA levels and outcomes in chronic hepatitis B［J］.Hepatology，2009，49(5 Suppl):S72-S84.

35 Lai CL， Yuen MF. Prevention of hepatitis B virus-related hepatocellular carcinoma with antiviral therapy［J］. Hepatology，2013，57(1):399-408.

36 Yin JH，Li N，Han YF，et al. Effect of antiviral treatment with nucleotide/nucleoside analogs on postoperative prognosis of hepatitis B virus-related hepatocellular carcinoma:a two-stage longitudinal clinical study［J］. J Clin Oncol，2013，31(29):3647-3655.

37 Huang G，Lai EC， Lau WY， et al. Posthepatectomy HBV reactivation in hepatitis B-related hepatocellular carcinoma influences postoperative survival in patients with preoperative low HBV-DNA levels［J］. Ann Surg，2013，257(3):490-505.

38 Hu TH，Chen CL，Lin CC，et al. Section 14. Combination of entecavir plus low-dose on-demand hepatitis B immunoglobulin is effective with very low hepatitis B recurrence after liver transplantation［J］. Transplantation，2014，97(Suppl 8):S53-S59.

39 Kim JM，Joh JW，Kim SJ，et al. Steroid withdrawal in adult liver transplantation:occurrence at a single center［J］. Transplant Proc，2010，42(10):4132-4136.

40 Sánchez-Fueyo A，Rimola A，Grande L，et al. Hepatitis B immunoglobulin discontinuation followed by hepatitis B virus vaccination:A new strategy in the prophylaxis of hepatitis B virus recurrence after liver transplantation［J］. Hepatology，2000，31(2):496-501.

41 Chung Mau Lo，Chi Leung Liu，See Ching Chan，et al. Failure of hepatitis B vaccination in patients receiving lamivudine prophylaxis after liver transplantation for chronic hepatitis B［J］. J Hepatol，2005，43(2):283-287.

42 Lo CM，Lau GK，Chan SC，et al. Efficacy of a pre-S containing vaccine in patients receiving lamivudine prophylaxis after liver transplantation for chronic hepatitis B［J］. Am J Transplant，2007，7(2):434-439.

43 Watt K，Veldt B，Charlton M. A practical guide to the management of HCV infection following liver transplantation ［J］. Am J Transplant，2009，9(8):1707-1713.

44 Vivarelli M，Cucchetti A，La Barba G，et al. Liver transplantation for hepatocellular carcinoma under calcineurin inhibitors:reassessment of risk factors for tumor recurrence［J］. Ann Surg，2008，248(5):857-862.

45 Chen K，Man K，Metselaar HJ，et al. Rationale of personalized immunosuppressive medication for hepatocellular carcinoma patients after liver transplantation［J］. Liver Transpl，2014，20(3):261-269.

46 Miyagi S，Kawagishi N，Sekiguchi S，et al. The relationship between recurrences and immunosuppression on living donor liver transplantation for hepatocellular carcinoma［J］. Transplant Proc，2012，44(3):797-801.

47 Saigal S，Shah S. Liver transplantation-economics in the less developed world［J］. Indian J Gastroenterol，2012，31(1):13-14.

48 Foroncewicz B，Mucha K，Ryszkowska E，et al. Safety and efficacy of steroid-free immunosuppression with tacrolimus and daclizumab in liver transplant recipients:6-year follow-up in a single center［J］.Transplant Proc，2009，41(8):3103-3106.

49 Vivarelli M，Cucchetti A，La Barba G，et al. Liver transplantation for hepatocellular carcinoma under calcineurin inhibitors:reassessment of risk factors for tumor recurrence［J］. Ann Surg，2008，248(5):857-862.

50 Nair S，Eason J，Loss G. Sirolimus monotherapy in nephrotoxicity due to calcineurin inhibitors in liver transplant recipients［J］. Liver Transpl，2003，9(2):126-129.

51 Menon KV，Hakeem AR，Heaton ND. Meta-analysis:recurrence and survival following the use of sirolimus in liver transplantation for hepatocellular carcinoma［J］. Aliment Pharmacol Ther，2013，37(4):411-419.

52 Liang W，Wang D，Ling X，et al. Sirolimus-based immunosuppression in liver transplantation for hepatocellular carcinoma:a meta-analysis［J］. Liver Transpl，2012，18(1):62-69.

53 Soliman T，Hetz H，Burghuber C，et al. Short-term induction therapy with anti-thymocyte globulin and delayed use of calcineurin inhibitors in orthotopic liver transplantation［J］. Liver Transplant，2007，13(7):1039-1044.

54 Martin-Mateos RM，Graus J，Albillos A，et al. Initial immunosuppression with or without basiliximab:a comparative study［J］.Transplant Proc，2012，44(9):2570-2572.

55 Pillai AA，Levitsky J. Overview of immunosuppression in liver transplantation［J］. World J Gastroenterol，2009，15(34):4225-4233.

56 Mazzaferro V，Llovet JM，Miceli R，et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria:a retrospective，exploratory analysis［J］. Lancet Oncol，2009，10(1):35-43.

57 Zimmerman MA，Ghobrial RM，Tong MJ，et al. Recurrence of hepatocellular carcinoma following liver transplantation:a review of preoperative and postoperative prognostic indicators［J］. Arch Surg，2008，143(2):182-188.

58 Xu J，Shen ZY，Chen XG，et al. A randomized controlled trial of Licartin for preventing hepatoma recurrence after liver transplantation［J］. Hematology，2007，5(2):269-276.

59 Huang L，Li GM，Zhu JY，et al. Efficacy of sorafenib after liver transplantation in patients with primary hepatic carcinoma exceeding the Milan criteria:a preliminary study［J］. Onco Targets Ther，2012，5:457-462.

60 Zhang Q，Chen H，Li Q，et al. Combination adjuvant chemotherapy with oxaliplatin， 5-fluorouracil and leucovorin after liver transplantation for hepatocellular carcinoma:a preliminary open-label study［J］. Invest New Drugs，2011，29(6):1360-1369.

61 張照輝，馬力文，宋世兵，等. 肝癌肝移植術(shù)后輔助化療的臨床分析［J］. 中華腫瘤雜志，2005，27(1):45-47.

62 Waghray A，Balci B，El-Gazzaz G，et al. Safety and efficacy of sorafenib for the treatment of recurrent hepatocellular carcinoma after liver transplantation［J］. Clin transplant，2013，27(4):555-561.

63 Pfeiffenberger J，Koschny R，Hoffmann K，et al. Sorafenib treatment is save and may affect survival of recurrent hepatocellular carcinoma after liver transplantation［J］. Langenbecks Arch Surg，2013，398(8):1123-1128.

64 Sposito C，Mariani L，Germini A，et al. Comparative efficacy of sorafenib versus best supportive care in recurrent hepatocellular carcinoma after liver transplantation:a case-control study［J］. J Hepatol，2013，59(1):59-66.

65 Hwang S，Kim YH，Kim DK，et al. Resection of pulmonary metastases from hepatocellular carcinoma following liver transplantation［J］. World J Surg，2012，36(7):1592-1602.

66 Taketomi A，F(xiàn)ukuhara T，Morita K，et al. Improved results of a surgical resection for the recurrence of hepatocellular carcinoma after living donor liver transplantation［J］. Ann Surg Oncol，2010，17(9):2283-2289.

67 Ko HK，Ko GY，Yoon HK，et al. Tumor response to transcatheter arterial chemoembolization in recurrent hepatocellular carcinoma after living donor liver transplantation［J］. Korean J Radiol，2007，8(4):320-327.

68 Ho CK，Chapman WC，Brown DB. Radiofrequency ablation of recurrent hepatocellular carcinoma in a patient after liver transplantation:two-year follow-up［J］. J Vasc Interv Radiol，2007，18(11):1451-1453.