引用本文： 四川大學華西醫院肝癌MDT團隊. 肝細胞癌切除術后復發轉移的防治：華西醫院多學科專家共識. 中國普外基礎與臨床雜志, 2017, 24(8): 927-939. doi: 10.7507/1007-9424.201708006 復制
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0 前言
肝細胞癌（hepatocellular carcinoma，HCC）在全球惡性腫瘤發病率排第 6 位，每年新發 HCC 病例和死亡病例 50% 以上在中國[1]。我國的最新數據[2]表明：HCC 發病率居惡性腫瘤第 4 位，而病死率居第 3 位。HCC 的外科治療是 HCC 患者獲得長期生存最重要的手段，包括肝切除術與肝移植術。但 HCC 切除術后 5 年復發轉移率高達 40%～70%[3]。如果能夠充分認識 HCC 切除術圍手術期規范化處理的重要性，加強 HCC 復發轉移的基礎與臨床研究，有望改善 HCC 的總體預后。HCC 切除術的規范首先涉及到 HCC 的生物學特征、背景肝病，涉及到 HCC 切除術前評估、復發預測、手術操作，還涉及到術后監測與治療。多學科綜合治療協作組（multidisciplinary team，MDT）通過多學科的協同診斷與治療，最大限度地發揮各個學科的專業優勢，使患者獲益最大化。因此，華西醫院 HCC 的 MDT 團隊，結合自己的體會[4]以及國內外學者的經驗，經反復討論，首次對 HCC 切除術后復發轉移的防治達成了共識。隨著新的循證醫學證據的不斷出現，作為初始版本，本共識仍有待全國專家的不斷更新和完善。
本共識中的證據等級分為 6 級，推薦意見為 5 級[5-6]，見表 1 和表 2。
表1
證據等級
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| 證據級別 | 描述 |
| Ⅰa | 證據源于對多項隨機對照研究的 meta 分析結果 |
| Ⅰb | 證據源于至少一項設計良好的隨機對照研究結果 |
| Ⅱa | 證據源于至少一項設計良好的前瞻性非隨機對照研究結果 |
| Ⅱb | 證據源自至少一項設計良好的其他類型干預性臨床研究結果 |
| Ⅲ | 證據源于設計良好的非干預性研究，如描述性研究、相關性研究等 |
| Ⅳ | 證據源于專家委員會報告或權威專家的臨床經驗報道 |
表2
推薦意見級別
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| 證據等級 | 描述 |
| A | 良好的科學證據提示該醫療行為帶來明確獲益，建議醫師對患者實施該醫療行為 |
| B | 現有證據表明該醫療行為可帶來中度獲益，超過其潛在風險；醫師可建議對患者實施該醫療行為 |
| C | 現有證據表明該醫療行為可能獲益較小，或獲益與風險接近；醫師可根據患者個體情況有選擇地向患者建議或實施該醫療行為 |
| D | 現有證據表明該醫療行為無獲益，或其潛在風險超過獲益；醫師不宜向患者實施該醫療行為 |
| E | 缺乏科學證據，或現有證據無法評價該醫療行為的獲益與風險；醫師應幫助患者理解該醫療行為存在的不確定性 |
1 HCC 與復發 HCC 的診斷標準及術前評估目標
1.1 臨床診斷標準
國際上公認，可以采用臨床診斷標準的實體瘤，唯有 HCC。臨床診斷 HCC 主要依據三個方面：即慢性肝病背景、影像學特征和血清 AFP 水平。因 HCC 巨大的異質性，影像學表現復雜多樣，AFP 水平差異較大，因此在實際應用時應綜合分析，嚴格掌握標準。目前國際上公認的臨床診斷標準為：同時滿足以下條件中的 1.1.1+1.1.2.1+1.1.3 三項或 1.1.1+1.1.2.2 兩項；否則，應進一步行穿刺活檢[3, 7-8]。
1.1.1 肝炎肝硬化史 具有肝硬化以及 HBV 和（或）HCV 感染〔HBV 和（或）HCV 抗原陽性〕的證據。
1.1.2 典型的 HCC 影像特征 MRI 和（或）CT 動脈增強掃描或增強多期掃描顯示肝內病灶在動脈期不均勻或均勻，即富血供（arterial hypervascularity），而門靜脈期或延遲期快速洗脫（venous or delayed phase washout）。MRI 肝膽特異性對比劑普美顯增強掃描，動脈期均勻或不均勻強化、門靜脈期無快速洗脫，但肝膽期無強化；或動脈期無強化，門靜脈期無強化或輕度強化，肝膽期無強化，且病灶在高 b 值 DWI 圖像呈高信號。
1.1.2.1 如果肝臟病灶直徑為 1～2 cm，需要 CT 和 MRI 兩項檢查且都顯示具有 HCC 典型影像特征，可診斷 HCC，以加強診斷的特異性。
1.1.2.2 如果肝臟病灶直徑>2 cm，CT 和 MRI 兩項檢查中有一項顯示肝臟占位具有 HCC 典型影像特征，即可診斷 HCC。
1.1.3 AFP水平升高 血清 AFP≥400 μg/L 持續 1 個月或≥200 μg/L 持續 2 個月，并能排除其他原因引起的 AFP 升高，包括妊娠、生殖系胚胎源性腫瘤、活動性肝病及繼發性肝癌等。
1.2 病理學診斷標準
肝臟占位病變或者肝外轉移灶的穿刺活檢組織或手術切除標本，經細胞學和（或）病理組織學檢查診斷為 HCC，此為診斷的金標準。
1.3 復發 HCC 的診斷標準
與初次 HCC 診斷標準相同，甚至要求 2 種影像學檢查顯示 HCC 的血供特征[3, 8-13]。2 種甚至 3 種影像學檢查可優勢互補[3]，對準確的 HCC 分期、預后預測和幫助選擇最佳治療方式具有積極意義。
在慢性肝病背景下，肝內實性病灶的定性，推薦采用 MRI 肝膽特異性對比劑增強掃描，對鑒別治療后壞死灶、出血灶、再生結節以及 HCC 復發，是目前國際上公認的準確的影像學檢查方法。
2 HCC 肝切除術前腫瘤標志物、影像學及其他預測術后高危復發的指標
① 術前 AFP 水平：術前 AFP 明顯升高（≥400 μg/L）較不升高或升高不明顯患者的預后更差[14-16]。② 影像學檢查：影像學檢查顯示突破包膜生長、呈多結節融合樣生長或無包膜的 HCC 較單結節生長方式的 HCC 預后更差[17-19]；影像學檢查顯示單個 HCC 直徑大于 5 cm 或多結節 HCC 伴有更高的脈管內癌栓（MVI）發生率[20-21]；影像學檢查顯示腫瘤內動脈是 MVI 的危險因素[22]；影像學檢查顯示或手術中發現門靜脈癌栓提示預后不良[23-24]；靜脈癌栓和（或）淋巴結轉移患者不宜接受肝移植[25]；術前影像學檢查顯示 4 個及以上的多結節 HCC 手術切除不能生存獲益[25]。③ HCC 干細胞標志物高表達[26]和 EpCAM- CTC7.5≥2[27]提示預后不良。④ 術前 3 個腫瘤標志物包括 AFP、甲胎蛋白異質體（AFP-L3） 和 γ-羧基凝血酶原（des-gamma-carboxy prothrombin，DCP）都升高的 HCC 患者，預后更差[28]。有研究[29]顯示，HCC 病灶直徑為 3.6 cm、DCP 為 101 mAU/mL 和最大標準攝取值（SUVmax）為 4.2 以上時，預測 MVI 的敏感度與特異度分別是 100% 和 90.9%。
3 HCC 切除術中預防復發的措施
① 對位于右肝或左肝的大 HCC 病灶，特別是影像學檢查提示膈肌受侵者，應行前入路肝切除[4, 30]，不宜先行游離肝臟。② 對預估斷肝時出血量可能達到 600～800 mL 者，應行入肝血流阻斷或半入肝血流阻斷[31-32]。術中大量出血將影響患者的預后[33]，而入肝血流阻斷不會影響腫瘤患者的預后[34]。③ 術中超聲檢查甚至超聲造影[35]在 HCC 的手術中是需要的，可進一步顯示腫瘤旁有無衛星結節、有無癌栓、余肝有無結節，以及病灶與第 1、第 2 和第 3 肝門的關系，以幫助確定切線與切緣距離。④ 若術中發現明確或可疑病灶，應考慮同時切除或行射頻治療[36]。⑤ 根據預測的殘肝體積、ICGR15、肝硬化程度和腫瘤范圍應首先選擇解剖性肝切除，其次才考慮寬切緣非規則性肝切除或腫瘤局部切除術[37-38]。
4 HCC 根治性切除標準[3 , 11 , 35 , 39 ]
4.1 術中判斷標準
① 肝靜脈、門靜脈、膽管以及下腔靜脈未見肉眼癌栓；② 無鄰近臟器侵犯，無肝門淋巴結轉移或遠處轉移；③ 腫瘤切緣>1 cm，若切緣<1 cm，但切除的肝斷面組織學檢查無腫瘤細胞殘留，即切緣陰性；④ 術中超聲檢查未發現有衛星灶、小脈管癌栓、新病灶等。
4.2 術后病理報告判斷標準
規范性病理取材和病理報告[21]未報 MVI、衛星結節、切緣陽性等。
4.3 術后 2 個月判斷標準
① 術后 2 個月行超聲、CT、MRI（必須有其中兩項）檢查未發現腫瘤病灶；② 若術前 AFP 升高，則要求術后 2 個月時需行 AFP 定量測定，其水平在正常范圍（極個別患者 AFP 降至正常的時間超過 2 個月）。
5 HCC 切除術后伴有高危復發因素患者的預測、監測與治療
5.1 復發的高危因素
HCC 切除術后 1～2 個月，應結合 AFP 和 DCP 下降情況以及手術和病理報告情況，再次評估患者的高危復發因素，交待應該實施的輔助治療，甚至可作出基本預測。如對于單個大病灶的 HCC，血小板淋巴細胞比（PLR）小于 107，MVI 陽性和腫瘤直徑≥6.8 cm 這 3 個因素同時存在時提示預后差[40]。導致 HCC 術后復發的危險因素很多，包括 ① 手術因素：非解剖型肝切除[41]、手術切緣殘留[42]、較大量的出血和輸血[43]、手術擠壓腫瘤等；② 臨床病理因素：腫瘤低分化、較晚的腫瘤分期、腫瘤破裂[44]、無完整包膜、腫瘤直徑大于 5 cm、腫瘤數目≥3 個[45]、脈管侵犯（包括脈管癌栓或膽管癌栓）[46]、淋巴結轉移[47]、衛星灶、鄰近器官受侵、AFP 明顯升高[46]、AFP 術后 2 個月未降至正常水平[48]、術后血管造影殘存陽性病灶。③ 背景肝病因素：包括病毒性肝炎活躍、肝硬化程度等。
推薦 1：肉眼癌栓、MVI、多個腫瘤、衛星結節、淋巴結轉移、AFP 術后 2 個月未降至正常水平和術后血管造影殘存陽性病灶是明確的肝癌復發高危風險，應考慮術后輔助治療（證據等級Ⅱb；推薦意見級別 B）
5.2 HCC 切除術后患者的隨訪
對 HCC 患者術后應進行定期隨訪。隨訪的監測內容主要是肝臟影像學檢查、HCC 標志物（AFP 和 DCP）檢查、HBV-DNA 和肝功能檢查[7-8, 49]。
推薦 2：乙肝相關性 HCC 隨訪頻率在術后 2 年內應每 3～4 個月 1 次；2 年以后，可每 4～6 個月 1 次；5 年以后依然正常，可每 6 個月隨訪 1 次（證據等級Ⅳ；推薦意見級別 B）
5.3 HCC 切除術后伴有高危復發因素患者的治療
目前證據[50-53]表明，對沒有復發高危因素的患者采取不恰當的輔助治療，如 TACE，可能引起殘余肝臟的損害，導致肝功能惡化而致生活質量下降，長期生存受影響，甚至可使肝外轉移的發生率升高，預后更差。
推薦 3：不伴復發高危因素的患者，除系統的抗病毒治療（乙肝丙肝相關 HCC）外，目前不推薦術后輔助治療（證據等級Ⅳ；推薦意見級別 B）
對于 HCC 切除術后伴有復發高危因素的患者，目前尚無較統一的預防腫瘤復發治療方式的推薦。已有較多研究[50-51, 54]顯示，對有殘余病灶和早期復發風險、多結節、腫瘤直徑>5 cm 以及有血管侵犯的 HCC 切除術后患者，術后行 TACE 輔助治療，可使患者生存獲益。
對伴有復發高危因素患者可根據具體情況選擇以下的綜合治療，包括：TACE[23, 51, 53-57]、抗病毒治療[58-60]、胸腺肽 α1[61-63]或 α-干擾素[64-67]的免疫調理治療、索拉非尼[68-70]以及維生素 K2[71-75]治療。其次還可考慮選擇單用或聯合化療等[76-77]。
推薦 4：對伴有復發高危因素患者，術后根據情況選擇 TACE、胸腺肽 α1 或 α-干擾素、索拉非尼、維生素 K2 等輔助治療（證據等級Ⅱb；推薦意見級別 A）
6 HCC 切除術后肝內復發模式及臨床意義
目前廣泛認可的復發性肝細胞癌（recurrent hepatocellular carcinoma，RHCC）來源于：① 原發性肝細胞癌（primary hepatocellular carcinoma，PHCC）切除后，肉眼難以查見的殘留腫瘤細胞繼續生長或通過肝內血運播散形成的肝內轉移（intrahepatic metastasis，IM）；② 由于 HBV 或 HCV 感染，肝臟在長期慢性炎癥反應及肝硬化背景下，正常肝細胞或癌旁細胞染色體長期累積突變而發生的惡性轉化，形成多中心發生（multicentric occurrence，MO）的 RHCC。
最早的鑒別方法是基于臨床病理資料的總結，根據 HCC 復發時間，將 1 年內復發的 HCC 定為 IM，1 年以上復發的 HCC 定為 MO[78]。也有基于病理診斷判定 IM 的的標準[79]，及基于腫瘤的分化情況提出的 MO 鑒別方法[80-81]。但其敏感度和特異度均不理想，很大程度上受到病理醫生主觀因素的影響。隨著分子生物學技術及基因組學技術的發展，臨床及病理學者對 RHCC 來源探索了比較多的鑒別方法，包括微衛星雜合性缺失模式（loss of heterozygosity，LOH），微衛星不穩定性檢測（microsatellite instability），p53 基因點突變模式分析（TP53 gene mutation analysis），X 染色體失活性分析（X chromosome inactivation analysis），HBV-DNA 整合位點檢測（HBV-DNA integration detection），DNA 甲基化模式檢測（DNA methylation analysis），miRNA 譜試分析、比較基因組雜交分析（comparative genomic hybridization，CGH）等[82-91]。有學者[92-93]綜合多組學的方法并聯合臨床病理資料，鑒定探討多結節 HCC 的發生來源及腫瘤異質性。其中 LOH 運用廣泛。微衛星 DNA 是反應細胞 DNA 整體穩定性的良好標志，聯合多個高頻 LOH 染色體能提高鑒別 RHCC 的準確性。所需標本條件較易達到，甲醛固定石蠟包埋的樣本或穿刺標本都可滿足檢測要求[82]。
推薦 5：對于不同來源 RHCC 應采取不同的治療方法。MO 的總體生存率好于 IM。對于 IM 應選擇介入及靶向藥物治療，而對于 MO 再次手術切除或肝移植治療可能會獲得與首次切除相同的療效（證據等級Ⅱb；推薦意見級別 B）
7 HCC 切除術后肝內復發患者的外科治療
7.1 可切除性 RHCC 的再切除
有研究[94-95]顯示，肝切除術后的可切除性 RHCC，再次肝切除者總生存率（OS）優于 TACE 治療者；系統評價也得出了相同的結論[96]，甚至有研究[97-98]認為患者能夠從第 3 次手術切除中生存獲益。而第 4 次肝切除并不會改善患者的生存情況[99]。對于可切除的肝外轉移，手術切除同樣能夠給患者帶來生存獲益[100]。RHCC 患者再次手術的預后與患者初次手術時的臨床病理特征、復發間隔時間等密切相關[101]。再次切除患者最好是初次手術時腫瘤單發、腫瘤復發的間隔時間≥1 年，且復發時腫瘤無血管侵犯[101]。
7.1.1 可切除性 RHCC 患者的術前評估 RHCC 患者再次術前評估與初次術前評估一樣，應考慮患者的體能狀態、肝功能、儲備功能、肝硬化程度、門靜脈高壓程度、剩余肝臟體積等[97, 102-104]。再次肝切除要求患者的 PS 評分為 0～1 分，無明顯心、肺、腦、腎等重要器官功能障礙；肝功能為 Child-Pugh 分級為 A 級或者肝功能為 B 級但經短期護肝治療后恢復到 A 級；肝臟儲備功能良好。患者的剩余肝臟體積（FLV）應結合患者的肝功能、肝臟儲備功能等多項指標綜合考慮[105]。對于伴肝硬化、Child-Pugh A 級、ICG R15<10% 的患者，FLV 應>40%；對 ICG R15 為 10%～20% 的患者，FLV 應>50%[106-108]。對于肝纖維化患者，FLV 應>30%；而對于正常肝臟患者，FLV 應>20%[109]。高齡患者經嚴格評估后，再次肝切除同樣是安全可行的[110]。
推薦 6：RHCC 患者能夠從再次或多次手術切除治療中生存獲益。但術前應嚴格評估患者的肝功能、肝儲備功能、剩余肝臟體積等。證據等級（證據等級Ⅱb；推薦意見級別 B）
7.1.2 可切除性 RHCC 的腹腔鏡手術 與傳統手術相比，腹腔鏡肝切除術具有創傷小、術后恢復快等優點。許多研究[111-115]亦證實，對于 RHCC 患者，腹腔鏡手術后無瘤生存率及總體生存率與傳統開腹手術比較無明顯差異。但值得注意的是，這些研究中，許多腹腔鏡手術對患者的腫瘤大小、位置等是有選擇性的[112-113, 116]。最近一項多中心研究證實，對于腹腔鏡肝切除術中中轉開腹的患者術中出血量及輸血量、術后住院時間、并發癥發生率和死亡率均明顯增加或延長[117]。
推薦 7：對于 RHCC 患者，有經驗的中心仍然可以選擇腹腔鏡肝切除術。但應嚴格掌握適應證，避免不必要的中轉開腹（證據等級Ⅱb；推薦意見級別 B）
7.2 肝內 RHCC 的消融治療
局部消融治療的消融方式包括：射頻消融（RFA）、微波消融（MWA）、高功率超聲聚焦消融（HIFU）、冷凍治療（CRA）、無水乙醇注射治療（PEI）等[118-120]。
較多研究[121-125]顯示，HCC 切除術后復發患者可以從 RFA 中獲益，甚至可取得與再切除相似的 OS 及無瘤生存率（DFS），而與切除相比，RFA 的明顯優勢在于微創、并發癥少、可重復施行性強，還可忽略首次手術后是否存在復發高危因素或復發時間。RHCC 患者 RFA 前評估與初診 HCC 的 RFA 前評估相似[126-127]。對于 RHCC，其 RFA 治療的指征[128]為：單個腫瘤直徑≤5 cm；腫瘤數目≤3 個且最大直徑≤3 cm；不伴有脈管內癌栓或鄰近器官受侵；超聲顯示有射頻路徑，腫瘤可達到完全消融。需要特別注意的是，對于直徑超過 3 cm 的腫瘤，RFA 中應采用多點覆蓋，以確保病灶完全消融[129]，或選擇 MWA[130-135]。
有較多研究比較了 CRA、RFA 和 MWA 治療腫瘤直徑<5 cm 的 HCC 的療效，結果發現其 OS 和 DFS 無差異，但對于直徑為 3～4 cm 的腫瘤，CRA 術后局部復發率較 RFA 更低[136-137]。有研究[138]提示，HIFU 和 RFA 對于符合米蘭標準的 RHCC 治療效果相當；而 PEI 對腫瘤直徑≤2 cm 的 HCC 消融效果確切[139-142]。
推薦 8：肝內 RHCC 患者能夠從消融治療中生存獲益，有條件的中心應根據術前評估選擇適當的消融方式、采取規范的消融流程，避免腫瘤消融不完全或副損傷（證據等級 Ia；推薦意見級別 A）
7.3 肝內 RHCC 的肝移植
許多研究[143-146]報道，對于 RHCC 患者行挽救性肝移植可以生存獲益。甚至有研究[143, 145]認為，對RHCC 患者行挽救性肝移植，其 OS 明顯優于行再次切除者。在這些研究中，患者初次手術時的腫瘤大小符合米蘭標準[144, 146-148]，也有初次手術時患者的腫瘤大小超過米蘭標準[149-150]；但絕大多數研究中，患者初次手術時均無大血管癌栓。在行挽救性肝移植時，大多數中心都要求腫瘤情況應符合米蘭標準[143-144, 147-148, 151]。但也有些中心采用擴展標準，如京都大學標準[152]、九州大學標準[145]、杭州標準[149]、up-to-7 標準[150]。許多研究[143, 145, 152]亦證實，對于 RHCC 患者，活體肝移植是安全有效的。但目前尚缺乏針對 RHCC 患者的尸體肝移植和活體肝移植預后比較的報道。
推薦 9：RHCC 患者能夠從肝移植中生存獲益，但腫瘤需符合特定的移植標準。行挽救性肝移植時，活體肝移植同樣是安全有效的（證據等級Ⅱa；推薦意見級別 B）
7.4 可切除性 RHCC 伴門靜脈癌栓的手術適應證
HCC 合并門靜脈癌栓是否應接受手術切除一直存在較大爭議。近年來，有較多文獻報道此類患者中有部分患者可從手術中獲益。亞太地區學者[49, 153-154]認為，對于部分 HCC 合并門靜脈癌栓的患者應考慮手術切除，但應重視患者的篩選。對于 RHCC 伴門靜脈癌栓患者，更應嚴格把握此類患者手術切除的適應證。首次，根治性切除術后復發時間大于 1 年，為可切除性復發腫瘤，估計癌栓形成的時間比較短尚未發生機化，門靜脈癌栓分型屬于Ⅰ、Ⅱ或Ⅲ型，適合肝段、肝葉等解剖性肝切除，可考慮行肝葉、半肝等解剖性肝切除術加門靜脈取栓術[24]。但 HCC 合并Ⅲ型門靜脈癌栓患者的預后更差，應慎重選擇[155]。
推薦 10：對于肝內 RHCC 伴門靜脈癌栓患者，在綜合評估、嚴格掌握指征的基礎上仍可考慮手術治療（證據等級Ⅲ；推薦意見級別 B）
7.5 可切除性 RHCC 伴膽管癌栓的手術適應證
對初次手術切除 HCC 不伴 MVI 等復發高危因素、復發時間在 1 年以上的 HCC 肝內復發伴膽管癌栓的患者，原則上應爭取外科手術完整切除腫瘤及取盡癌栓，特別是對那些不伴梗阻性黃疸的患者[156-159]。對腫瘤個數小于 3 個，局限在肝段或肝葉，預估有足夠的殘余肝體積，癌栓位于腫瘤側膽管者，可行腫瘤及癌栓累及膽管的解剖性肝切除。對 RHCC 可切除，癌栓進入膽總管，癌栓形成時間較短尚未發生機化者，可行肝葉、半肝等的解剖性肝切除術加膽管探查癌栓取出術加 T 管引流術[158, 160-161]；對癌栓形成時間長，但癌栓局限在肝外膽管，RHCC 可切除者，可考慮行肝切除術加肝外膽管切除術加膽腸吻合術[11, 156]。
推薦 11：初次 HCC 不合并 MVI 等復發高危因素，RHCC 可切除，癌栓位于腫瘤側膽管，推薦行解剖性肝切除術。對于合并膽總管癌栓患者，應謹慎選擇外科手術（證據等級Ⅲ；推薦意見級別 B）。
7.6 可切除性 RHCC 伴腔靜脈癌栓的手術適應證
手術切除腫瘤和取盡腔靜脈癌栓、降低栓子脫落導致突發死亡的風險，是目前唯一可能治愈 RHCC 合并腔靜脈癌栓患者的手段[162-163]。對腫瘤個數小于 3 個，局限在肝段或肝葉，術前評估有足夠的肝體積，癌栓未延伸至心房，腔靜脈癌栓形成時間較短尚未發生機化者[162]，可行肝切除加全肝血流隔離下取盡腔靜脈癌栓；如癌栓延伸到右心房，應在體外循環下取盡心房及腔靜脈的癌栓[164]。RHCC 伴腔靜脈癌栓手術風險高，預后不確定，指征宜從嚴掌握。初次 HCC 切除 2 年以上，不伴 MVI 等高危復發因素，術前對 TACE 反應良好者更適合接受這類手術[165]。
推薦 12：可切除性 RHCC 合并腔靜脈癌栓患者，特別是復發癌對 TACE 反應良好者，推薦 HCC 切除加癌栓取出術（證據等級Ⅲ；推薦意見級別 B）。同時合并門靜脈癌栓者不建議手術治療（證據等級Ⅲ；推薦意見級別 B）
7.7 可切除性 RHCC 伴肝硬化、門靜脈高壓癥、脾大脾功能亢進聯合脾切除術適應證
肝內 RHCC 具可切除性，伴中、重度脾腫大，重度脾功能亢進（WBC <3×109/L，PLT<50×109/L）表現者，應考慮行 HCC 切除聯合脾切除術[166-171]。對有明顯食管胃底靜脈曲張，特別是發生過食管胃底曲張靜脈破裂大出血的患者，經過嚴格的評估后還應同時行賁門周圍血管離斷術。對有嚴重胃黏膜病變患者，如果患者術中情況允許，應行脾腎分流術或其他類型的選擇性門腔分流術。此類患者都應考慮將來行肝移植的可能性，故應慎行斷流術或分流術。此類聯合手術宜從嚴掌握，如患者有既往肝功能不全、凝血功能障礙等病史，應考慮行挽救性肝移植。
推薦 13：肝內 RHCC 伴肝硬化門靜脈高壓癥中、重度脾大脾功能亢進可聯合脾切除術，但應嚴格評估患者的肝功能、肝儲備功能（證據等級Ⅳ；推薦意見級別 B）
8 RHCC 的介入治療
以往的 RCT 研究結果[172-173]顯示，病灶局限在肝內而且沒有血管侵襲的 HCC 患者可以從 TACE 治療中獲益。TACE 雖然不是治療 HCC 的根治性手段，但有約 10% 的 HCC 患者在接受序貫 TACE 治療后獲得完全緩解[174]。對于 RHCC 病灶數目≤3 個，腫瘤直徑≤5 cm 的患者，TACE 和 RFA 的效果相當[175]，尤其是對于切除或移植術后有多處肝內復發的患者，TACE 是降低復發后死亡率的重要手段[176]。還有研究結果[95]顯示，符合米蘭標準的 RHCC，早期復發時 TACE 和 RFA/切除具有相同的效果；后期復發時， RFA/切除效果好于 TACE。Jin 等[177]比較了 TACE、切除和 RFA 治療對伴有 MVI 的 RHCC 的治療效果，結果顯示， TACE 治療 MVI 陽性的 RHCC 患者可以獲得較切除和 RFA 治療更好的 OS 和 DFS，特別是對于 1 年內復發的 MVI 陽性患者，OS 顯著高于切除組和 RFA 組。Yang 等[178]回顧性研究了 TACE 聯合 RFA 與單獨行 TACE 或 RFA 治療 RHCC 的效果，聯合治療組患者的治療成功率和 5 年生存率都顯著高于單獨 TACE 組或 RFA 組。因此，TACE 治療的指征有[122,179]：①RHCC 病灶臨近重要血管或膽管而無法行切除或 RFA 治療；② 肝內多發復發腫瘤；③ 早期肝內 RHCC（1 年內）；④ 患者個人選擇 TACE 治療。
推薦 14：對于早期肝內 RHCC（肝切除術后 1 年內）、病灶臨近重要血管或膽管而無法行切除或消融治療的 RHCC、肝內多個 RHCC 病灶，TACE 可控制 HCC 進展，帶來生存獲益（證據等級Ⅱa；推薦意見級別 A）
9 RHCC 的放射治療
放療是治療 RHCC 有效和安全的手段之一[180-181]，國內外研究報道，小肝癌行放療 5 年生存率可達 60% 以上[182-183]，甚至療效等同于 RFA 治療[184]，但與手術相比尚無直接證據。RHCC 患者常面臨腫瘤位于切除困難位置、巨大、多發、大血管癌栓形成及肝功能失代償等因素，也常伴發肺、骨等部位的肝外轉移，對此可根據腫瘤的情況選擇合適的放療方式，可多次實施以縮小肝內外病灶，控制腫瘤進展，減輕腫瘤引起的癥狀，延長患者生存時間。如肺轉移患者經體外放射治療其 2 年生存率可達 70.7%，骨轉移患者經體外放射治療其中位生存期達到 7.4 個月[185-191]。對于 HCC 肝移植術后復發患者，可有效控制復發癌的進展。放療也可聯合介入治療改善晚期 RHCC 患者的預后[192]。
HCC 患者接受 TACE 聯合阿霉素載藥緩釋微球[193]和放射微球[194]治療能獲得更高的腫瘤壞死率和更低的腫瘤進展率。但其在 RHCC 中的作用尚待研究。
推薦 15：復發性小肝癌且不宜手術切除者，可選擇放射治療（證據等級Ⅱb，推薦意見級別 B）；RHCC 合并肝外轉移者也可選擇放射治療（證據等級Ⅲ；推薦意見級別 B）
10 HCC 切除術后復發的全身治療[3 ]
10.1 抗病毒治療
TACE、手術和化療均可引起乙型肝炎病毒復燃，而且抗病毒治療可以降低 TACE 及手術之后的復發率，改善患者的生存。因此，對合并有乙肝病毒感染且復制活躍的 HCC 患者，推薦口服核苷（酸）類似物抗病毒治療[58, 60]。
10.2 抗腫瘤治療
10.2.1 分子靶向藥物 索拉非尼是國際公認的治療晚期 HCC 的分子靶向藥物。兩項大型國際多中心Ⅲ期臨床試驗均證明了索拉非尼對于不同國家地區、不同肝病背景的晚期 HCC 具有一定的生存獲益[70]。近來，瑞戈非尼已獲批成為晚期 HCC 的二線分子靶向藥物。
10.2.2 系統化療 奧沙利鉑在我國被批準用于治療不適合手術切除或局部治療的 HCC[195]。適應證主要為：① 合并有肝外轉移的晚期患者；② 雖為局部病變，但不適合手術治療和 TACE 者；③ 合并門靜脈主干或下腔靜脈瘤栓者；④ 多次 TACE 后血管阻塞和（或）TACE 治療后復發的患者。
10.2.3 免疫治療 HCC 的免疫治療主要包括免疫調節劑（胸腺肽 α1、干擾素 α 等）[62, 196]、免疫檢查點阻斷劑（CTLA-4 阻斷劑、PD-1/PD-L1 阻斷劑等）、腫瘤疫苗（樹突細胞疫苗等）和細胞免疫治療[197]。這些治療手段均有一定的抗腫瘤作用，但尚待大規模的臨床研究驗證。
10.2.4 中醫中藥 中醫中藥治療能夠改善癥狀，提高機體的抵抗力，減輕放化療的不良反應，提高生活質量。但缺乏高級別的循證醫學證據。
10.3 對癥支持治療
適度的康復運動、積極鎮痛、改善睡眠、增加營養、心理治療等對癥支持治療可增強機體的免疫功能，改善患者的生活質量和預后。
11 HCC 切除術后復發的綜合治療
目前在中國，HCC 診治領域的特點仍然是多方法、多學科共存，而以治療手段建科的分科診療體制與實現有序規范的 HCC 治療之間存在一定的矛盾[3]。因此，HCC 的 MDT 下的合理規范的治療方法選擇與綜合治療就顯得極其重要，特別是對 RHCC 的治療。已進行抗病毒治療的 HCC 切除術后伴有復發高危風險患者，聯合 TACE、索拉非尼與胸腺肽 α1 治療，還有肝內 RHCC 的 RFA 聯合 TACE 治療[178]等，都是綜合治療的典范，能讓患者更好的生存獲益。
12 展望
首先我們承認，本初始版本的共識，很多研究的循證醫學證據級別較低，但為了及時反映我國學者在 HCC 切除術后復發防治方面所做的不懈努力而取得的成果，有必要制訂適合我國國情的規范化方案，用于我們在處理 HCC 切除術后復發防治的患者時的參考。同時，新的循證醫學證據還在不斷涌現和補充，與 HCC 切除術后復發防治相關的很多隨機對照研究正在進行中，我們期望逐步完善該方面的共識。
為了進一步做好相關的研究及完善共識，在臨床實踐中應重視以下幾點原則：① MDT 是 HCC 診治的必然工作方式，通過積極有效的多學科綜合診治，HCC 切除術后復發的防治必將取得較大進展，從而改善 HCC 患者的總體預后。② HCC 切除術后復發為根治帶來巨大障礙，患者帶瘤生存時間和總體生存時間會作為療效評價的重要指標，我們讓患者在帶瘤生存的同時應努力提高他們的生命質量。③ 我國 HCC 切除術后復發患者多，病情復雜，通過開展更多的隨機對照研究來開發、驗證更多有效的 RHCC 的診斷與治療方法，并建立 RHCC 生物樣本庫，加強對 HCC 復發轉移的發生發展內在相關分子機制的研究，特別是 HCC 的分子分型、靶向治療和相關的轉化醫學的探索，將為精準治療提供更多證據，推動我國 HCC 防治事業的發展。
《肝細胞癌切除術后復發轉移的防治：華西醫院多學科專家共識》編審成員名單：
名譽組長：嚴律南
組 長：文天夫
成 員（以姓氏拼音為序）：
曹丹1，陳恩強2，陳衛霞3，陳哲宇4，黃紀偉4，蔣利4，李波4，李秋1，李志平1，魯昌立5，盧強6，盧武勝4，羅燕6，唐紅2，王文濤4，王辛1，魏永剛4，吳苾3，吳泓4，徐明清4，楊家印4，曾勇4，張鳴4（1：腫瘤中心；2：感染性疾病中心；3：放射科；4：肝臟外科；5：病理科；6：超聲診斷科）
編寫秘書：李川、劉暢、彭偉、張曉赟、彭馳涵、沈俊頤、金諶
0 前言
肝細胞癌（hepatocellular carcinoma，HCC）在全球惡性腫瘤發病率排第 6 位，每年新發 HCC 病例和死亡病例 50% 以上在中國[1]。我國的最新數據[2]表明：HCC 發病率居惡性腫瘤第 4 位，而病死率居第 3 位。HCC 的外科治療是 HCC 患者獲得長期生存最重要的手段，包括肝切除術與肝移植術。但 HCC 切除術后 5 年復發轉移率高達 40%～70%[3]。如果能夠充分認識 HCC 切除術圍手術期規范化處理的重要性，加強 HCC 復發轉移的基礎與臨床研究，有望改善 HCC 的總體預后。HCC 切除術的規范首先涉及到 HCC 的生物學特征、背景肝病，涉及到 HCC 切除術前評估、復發預測、手術操作，還涉及到術后監測與治療。多學科綜合治療協作組（multidisciplinary team，MDT）通過多學科的協同診斷與治療，最大限度地發揮各個學科的專業優勢，使患者獲益最大化。因此，華西醫院 HCC 的 MDT 團隊，結合自己的體會[4]以及國內外學者的經驗，經反復討論，首次對 HCC 切除術后復發轉移的防治達成了共識。隨著新的循證醫學證據的不斷出現，作為初始版本，本共識仍有待全國專家的不斷更新和完善。
本共識中的證據等級分為 6 級，推薦意見為 5 級[5-6]，見表 1 和表 2。
表1
證據等級
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| 證據級別 | 描述 |
| Ⅰa | 證據源于對多項隨機對照研究的 meta 分析結果 |
| Ⅰb | 證據源于至少一項設計良好的隨機對照研究結果 |
| Ⅱa | 證據源于至少一項設計良好的前瞻性非隨機對照研究結果 |
| Ⅱb | 證據源自至少一項設計良好的其他類型干預性臨床研究結果 |
| Ⅲ | 證據源于設計良好的非干預性研究，如描述性研究、相關性研究等 |
| Ⅳ | 證據源于專家委員會報告或權威專家的臨床經驗報道 |
表2
推薦意見級別
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| 證據等級 | 描述 |
| A | 良好的科學證據提示該醫療行為帶來明確獲益，建議醫師對患者實施該醫療行為 |
| B | 現有證據表明該醫療行為可帶來中度獲益，超過其潛在風險；醫師可建議對患者實施該醫療行為 |
| C | 現有證據表明該醫療行為可能獲益較小，或獲益與風險接近；醫師可根據患者個體情況有選擇地向患者建議或實施該醫療行為 |
| D | 現有證據表明該醫療行為無獲益，或其潛在風險超過獲益；醫師不宜向患者實施該醫療行為 |
| E | 缺乏科學證據，或現有證據無法評價該醫療行為的獲益與風險；醫師應幫助患者理解該醫療行為存在的不確定性 |
1 HCC 與復發 HCC 的診斷標準及術前評估目標
1.1 臨床診斷標準
國際上公認，可以采用臨床診斷標準的實體瘤，唯有 HCC。臨床診斷 HCC 主要依據三個方面：即慢性肝病背景、影像學特征和血清 AFP 水平。因 HCC 巨大的異質性，影像學表現復雜多樣，AFP 水平差異較大，因此在實際應用時應綜合分析，嚴格掌握標準。目前國際上公認的臨床診斷標準為：同時滿足以下條件中的 1.1.1+1.1.2.1+1.1.3 三項或 1.1.1+1.1.2.2 兩項；否則，應進一步行穿刺活檢[3, 7-8]。
1.1.1 肝炎肝硬化史 具有肝硬化以及 HBV 和（或）HCV 感染〔HBV 和（或）HCV 抗原陽性〕的證據。
1.1.2 典型的 HCC 影像特征 MRI 和（或）CT 動脈增強掃描或增強多期掃描顯示肝內病灶在動脈期不均勻或均勻，即富血供（arterial hypervascularity），而門靜脈期或延遲期快速洗脫（venous or delayed phase washout）。MRI 肝膽特異性對比劑普美顯增強掃描，動脈期均勻或不均勻強化、門靜脈期無快速洗脫，但肝膽期無強化；或動脈期無強化，門靜脈期無強化或輕度強化，肝膽期無強化，且病灶在高 b 值 DWI 圖像呈高信號。
1.1.2.1 如果肝臟病灶直徑為 1～2 cm，需要 CT 和 MRI 兩項檢查且都顯示具有 HCC 典型影像特征，可診斷 HCC，以加強診斷的特異性。
1.1.2.2 如果肝臟病灶直徑>2 cm，CT 和 MRI 兩項檢查中有一項顯示肝臟占位具有 HCC 典型影像特征，即可診斷 HCC。
1.1.3 AFP水平升高 血清 AFP≥400 μg/L 持續 1 個月或≥200 μg/L 持續 2 個月，并能排除其他原因引起的 AFP 升高，包括妊娠、生殖系胚胎源性腫瘤、活動性肝病及繼發性肝癌等。
1.2 病理學診斷標準
肝臟占位病變或者肝外轉移灶的穿刺活檢組織或手術切除標本，經細胞學和（或）病理組織學檢查診斷為 HCC，此為診斷的金標準。
1.3 復發 HCC 的診斷標準
與初次 HCC 診斷標準相同，甚至要求 2 種影像學檢查顯示 HCC 的血供特征[3, 8-13]。2 種甚至 3 種影像學檢查可優勢互補[3]，對準確的 HCC 分期、預后預測和幫助選擇最佳治療方式具有積極意義。
在慢性肝病背景下，肝內實性病灶的定性，推薦采用 MRI 肝膽特異性對比劑增強掃描，對鑒別治療后壞死灶、出血灶、再生結節以及 HCC 復發，是目前國際上公認的準確的影像學檢查方法。
2 HCC 肝切除術前腫瘤標志物、影像學及其他預測術后高危復發的指標
① 術前 AFP 水平：術前 AFP 明顯升高（≥400 μg/L）較不升高或升高不明顯患者的預后更差[14-16]。② 影像學檢查：影像學檢查顯示突破包膜生長、呈多結節融合樣生長或無包膜的 HCC 較單結節生長方式的 HCC 預后更差[17-19]；影像學檢查顯示單個 HCC 直徑大于 5 cm 或多結節 HCC 伴有更高的脈管內癌栓（MVI）發生率[20-21]；影像學檢查顯示腫瘤內動脈是 MVI 的危險因素[22]；影像學檢查顯示或手術中發現門靜脈癌栓提示預后不良[23-24]；靜脈癌栓和（或）淋巴結轉移患者不宜接受肝移植[25]；術前影像學檢查顯示 4 個及以上的多結節 HCC 手術切除不能生存獲益[25]。③ HCC 干細胞標志物高表達[26]和 EpCAM- CTC7.5≥2[27]提示預后不良。④ 術前 3 個腫瘤標志物包括 AFP、甲胎蛋白異質體（AFP-L3） 和 γ-羧基凝血酶原（des-gamma-carboxy prothrombin，DCP）都升高的 HCC 患者，預后更差[28]。有研究[29]顯示，HCC 病灶直徑為 3.6 cm、DCP 為 101 mAU/mL 和最大標準攝取值（SUVmax）為 4.2 以上時，預測 MVI 的敏感度與特異度分別是 100% 和 90.9%。
3 HCC 切除術中預防復發的措施
① 對位于右肝或左肝的大 HCC 病灶，特別是影像學檢查提示膈肌受侵者，應行前入路肝切除[4, 30]，不宜先行游離肝臟。② 對預估斷肝時出血量可能達到 600～800 mL 者，應行入肝血流阻斷或半入肝血流阻斷[31-32]。術中大量出血將影響患者的預后[33]，而入肝血流阻斷不會影響腫瘤患者的預后[34]。③ 術中超聲檢查甚至超聲造影[35]在 HCC 的手術中是需要的，可進一步顯示腫瘤旁有無衛星結節、有無癌栓、余肝有無結節，以及病灶與第 1、第 2 和第 3 肝門的關系，以幫助確定切線與切緣距離。④ 若術中發現明確或可疑病灶，應考慮同時切除或行射頻治療[36]。⑤ 根據預測的殘肝體積、ICGR15、肝硬化程度和腫瘤范圍應首先選擇解剖性肝切除，其次才考慮寬切緣非規則性肝切除或腫瘤局部切除術[37-38]。
4 HCC 根治性切除標準[3 , 11 , 35 , 39 ]
4.1 術中判斷標準
① 肝靜脈、門靜脈、膽管以及下腔靜脈未見肉眼癌栓；② 無鄰近臟器侵犯，無肝門淋巴結轉移或遠處轉移；③ 腫瘤切緣>1 cm，若切緣<1 cm，但切除的肝斷面組織學檢查無腫瘤細胞殘留，即切緣陰性；④ 術中超聲檢查未發現有衛星灶、小脈管癌栓、新病灶等。
4.2 術后病理報告判斷標準
規范性病理取材和病理報告[21]未報 MVI、衛星結節、切緣陽性等。
4.3 術后 2 個月判斷標準
① 術后 2 個月行超聲、CT、MRI（必須有其中兩項）檢查未發現腫瘤病灶；② 若術前 AFP 升高，則要求術后 2 個月時需行 AFP 定量測定，其水平在正常范圍（極個別患者 AFP 降至正常的時間超過 2 個月）。
5 HCC 切除術后伴有高危復發因素患者的預測、監測與治療
5.1 復發的高危因素
HCC 切除術后 1～2 個月，應結合 AFP 和 DCP 下降情況以及手術和病理報告情況，再次評估患者的高危復發因素，交待應該實施的輔助治療，甚至可作出基本預測。如對于單個大病灶的 HCC，血小板淋巴細胞比（PLR）小于 107，MVI 陽性和腫瘤直徑≥6.8 cm 這 3 個因素同時存在時提示預后差[40]。導致 HCC 術后復發的危險因素很多，包括 ① 手術因素：非解剖型肝切除[41]、手術切緣殘留[42]、較大量的出血和輸血[43]、手術擠壓腫瘤等；② 臨床病理因素：腫瘤低分化、較晚的腫瘤分期、腫瘤破裂[44]、無完整包膜、腫瘤直徑大于 5 cm、腫瘤數目≥3 個[45]、脈管侵犯（包括脈管癌栓或膽管癌栓）[46]、淋巴結轉移[47]、衛星灶、鄰近器官受侵、AFP 明顯升高[46]、AFP 術后 2 個月未降至正常水平[48]、術后血管造影殘存陽性病灶。③ 背景肝病因素：包括病毒性肝炎活躍、肝硬化程度等。
推薦 1：肉眼癌栓、MVI、多個腫瘤、衛星結節、淋巴結轉移、AFP 術后 2 個月未降至正常水平和術后血管造影殘存陽性病灶是明確的肝癌復發高危風險，應考慮術后輔助治療（證據等級Ⅱb；推薦意見級別 B）
5.2 HCC 切除術后患者的隨訪
對 HCC 患者術后應進行定期隨訪。隨訪的監測內容主要是肝臟影像學檢查、HCC 標志物（AFP 和 DCP）檢查、HBV-DNA 和肝功能檢查[7-8, 49]。
推薦 2：乙肝相關性 HCC 隨訪頻率在術后 2 年內應每 3～4 個月 1 次；2 年以后，可每 4～6 個月 1 次；5 年以后依然正常，可每 6 個月隨訪 1 次（證據等級Ⅳ；推薦意見級別 B）
5.3 HCC 切除術后伴有高危復發因素患者的治療
目前證據[50-53]表明，對沒有復發高危因素的患者采取不恰當的輔助治療，如 TACE，可能引起殘余肝臟的損害，導致肝功能惡化而致生活質量下降，長期生存受影響，甚至可使肝外轉移的發生率升高，預后更差。
推薦 3：不伴復發高危因素的患者，除系統的抗病毒治療（乙肝丙肝相關 HCC）外，目前不推薦術后輔助治療（證據等級Ⅳ；推薦意見級別 B）
對于 HCC 切除術后伴有復發高危因素的患者，目前尚無較統一的預防腫瘤復發治療方式的推薦。已有較多研究[50-51, 54]顯示，對有殘余病灶和早期復發風險、多結節、腫瘤直徑>5 cm 以及有血管侵犯的 HCC 切除術后患者，術后行 TACE 輔助治療，可使患者生存獲益。
對伴有復發高危因素患者可根據具體情況選擇以下的綜合治療，包括：TACE[23, 51, 53-57]、抗病毒治療[58-60]、胸腺肽 α1[61-63]或 α-干擾素[64-67]的免疫調理治療、索拉非尼[68-70]以及維生素 K2[71-75]治療。其次還可考慮選擇單用或聯合化療等[76-77]。
推薦 4：對伴有復發高危因素患者，術后根據情況選擇 TACE、胸腺肽 α1 或 α-干擾素、索拉非尼、維生素 K2 等輔助治療（證據等級Ⅱb；推薦意見級別 A）
6 HCC 切除術后肝內復發模式及臨床意義
目前廣泛認可的復發性肝細胞癌（recurrent hepatocellular carcinoma，RHCC）來源于：① 原發性肝細胞癌（primary hepatocellular carcinoma，PHCC）切除后，肉眼難以查見的殘留腫瘤細胞繼續生長或通過肝內血運播散形成的肝內轉移（intrahepatic metastasis，IM）；② 由于 HBV 或 HCV 感染，肝臟在長期慢性炎癥反應及肝硬化背景下，正常肝細胞或癌旁細胞染色體長期累積突變而發生的惡性轉化，形成多中心發生（multicentric occurrence，MO）的 RHCC。
最早的鑒別方法是基于臨床病理資料的總結，根據 HCC 復發時間，將 1 年內復發的 HCC 定為 IM，1 年以上復發的 HCC 定為 MO[78]。也有基于病理診斷判定 IM 的的標準[79]，及基于腫瘤的分化情況提出的 MO 鑒別方法[80-81]。但其敏感度和特異度均不理想，很大程度上受到病理醫生主觀因素的影響。隨著分子生物學技術及基因組學技術的發展，臨床及病理學者對 RHCC 來源探索了比較多的鑒別方法，包括微衛星雜合性缺失模式（loss of heterozygosity，LOH），微衛星不穩定性檢測（microsatellite instability），p53 基因點突變模式分析（TP53 gene mutation analysis），X 染色體失活性分析（X chromosome inactivation analysis），HBV-DNA 整合位點檢測（HBV-DNA integration detection），DNA 甲基化模式檢測（DNA methylation analysis），miRNA 譜試分析、比較基因組雜交分析（comparative genomic hybridization，CGH）等[82-91]。有學者[92-93]綜合多組學的方法并聯合臨床病理資料，鑒定探討多結節 HCC 的發生來源及腫瘤異質性。其中 LOH 運用廣泛。微衛星 DNA 是反應細胞 DNA 整體穩定性的良好標志，聯合多個高頻 LOH 染色體能提高鑒別 RHCC 的準確性。所需標本條件較易達到，甲醛固定石蠟包埋的樣本或穿刺標本都可滿足檢測要求[82]。
推薦 5：對于不同來源 RHCC 應采取不同的治療方法。MO 的總體生存率好于 IM。對于 IM 應選擇介入及靶向藥物治療，而對于 MO 再次手術切除或肝移植治療可能會獲得與首次切除相同的療效（證據等級Ⅱb；推薦意見級別 B）
7 HCC 切除術后肝內復發患者的外科治療
7.1 可切除性 RHCC 的再切除
有研究[94-95]顯示，肝切除術后的可切除性 RHCC，再次肝切除者總生存率（OS）優于 TACE 治療者；系統評價也得出了相同的結論[96]，甚至有研究[97-98]認為患者能夠從第 3 次手術切除中生存獲益。而第 4 次肝切除并不會改善患者的生存情況[99]。對于可切除的肝外轉移，手術切除同樣能夠給患者帶來生存獲益[100]。RHCC 患者再次手術的預后與患者初次手術時的臨床病理特征、復發間隔時間等密切相關[101]。再次切除患者最好是初次手術時腫瘤單發、腫瘤復發的間隔時間≥1 年，且復發時腫瘤無血管侵犯[101]。
7.1.1 可切除性 RHCC 患者的術前評估 RHCC 患者再次術前評估與初次術前評估一樣，應考慮患者的體能狀態、肝功能、儲備功能、肝硬化程度、門靜脈高壓程度、剩余肝臟體積等[97, 102-104]。再次肝切除要求患者的 PS 評分為 0～1 分，無明顯心、肺、腦、腎等重要器官功能障礙；肝功能為 Child-Pugh 分級為 A 級或者肝功能為 B 級但經短期護肝治療后恢復到 A 級；肝臟儲備功能良好。患者的剩余肝臟體積（FLV）應結合患者的肝功能、肝臟儲備功能等多項指標綜合考慮[105]。對于伴肝硬化、Child-Pugh A 級、ICG R15<10% 的患者，FLV 應>40%；對 ICG R15 為 10%～20% 的患者，FLV 應>50%[106-108]。對于肝纖維化患者，FLV 應>30%；而對于正常肝臟患者，FLV 應>20%[109]。高齡患者經嚴格評估后，再次肝切除同樣是安全可行的[110]。
推薦 6：RHCC 患者能夠從再次或多次手術切除治療中生存獲益。但術前應嚴格評估患者的肝功能、肝儲備功能、剩余肝臟體積等。證據等級（證據等級Ⅱb；推薦意見級別 B）
7.1.2 可切除性 RHCC 的腹腔鏡手術 與傳統手術相比，腹腔鏡肝切除術具有創傷小、術后恢復快等優點。許多研究[111-115]亦證實，對于 RHCC 患者，腹腔鏡手術后無瘤生存率及總體生存率與傳統開腹手術比較無明顯差異。但值得注意的是，這些研究中，許多腹腔鏡手術對患者的腫瘤大小、位置等是有選擇性的[112-113, 116]。最近一項多中心研究證實，對于腹腔鏡肝切除術中中轉開腹的患者術中出血量及輸血量、術后住院時間、并發癥發生率和死亡率均明顯增加或延長[117]。
推薦 7：對于 RHCC 患者，有經驗的中心仍然可以選擇腹腔鏡肝切除術。但應嚴格掌握適應證，避免不必要的中轉開腹（證據等級Ⅱb；推薦意見級別 B）
7.2 肝內 RHCC 的消融治療
局部消融治療的消融方式包括：射頻消融（RFA）、微波消融（MWA）、高功率超聲聚焦消融（HIFU）、冷凍治療（CRA）、無水乙醇注射治療（PEI）等[118-120]。
較多研究[121-125]顯示，HCC 切除術后復發患者可以從 RFA 中獲益，甚至可取得與再切除相似的 OS 及無瘤生存率（DFS），而與切除相比，RFA 的明顯優勢在于微創、并發癥少、可重復施行性強，還可忽略首次手術后是否存在復發高危因素或復發時間。RHCC 患者 RFA 前評估與初診 HCC 的 RFA 前評估相似[126-127]。對于 RHCC，其 RFA 治療的指征[128]為：單個腫瘤直徑≤5 cm；腫瘤數目≤3 個且最大直徑≤3 cm；不伴有脈管內癌栓或鄰近器官受侵；超聲顯示有射頻路徑，腫瘤可達到完全消融。需要特別注意的是，對于直徑超過 3 cm 的腫瘤，RFA 中應采用多點覆蓋，以確保病灶完全消融[129]，或選擇 MWA[130-135]。
有較多研究比較了 CRA、RFA 和 MWA 治療腫瘤直徑<5 cm 的 HCC 的療效，結果發現其 OS 和 DFS 無差異，但對于直徑為 3～4 cm 的腫瘤，CRA 術后局部復發率較 RFA 更低[136-137]。有研究[138]提示，HIFU 和 RFA 對于符合米蘭標準的 RHCC 治療效果相當；而 PEI 對腫瘤直徑≤2 cm 的 HCC 消融效果確切[139-142]。
推薦 8：肝內 RHCC 患者能夠從消融治療中生存獲益，有條件的中心應根據術前評估選擇適當的消融方式、采取規范的消融流程，避免腫瘤消融不完全或副損傷（證據等級 Ia；推薦意見級別 A）
7.3 肝內 RHCC 的肝移植
許多研究[143-146]報道，對于 RHCC 患者行挽救性肝移植可以生存獲益。甚至有研究[143, 145]認為，對RHCC 患者行挽救性肝移植，其 OS 明顯優于行再次切除者。在這些研究中，患者初次手術時的腫瘤大小符合米蘭標準[144, 146-148]，也有初次手術時患者的腫瘤大小超過米蘭標準[149-150]；但絕大多數研究中，患者初次手術時均無大血管癌栓。在行挽救性肝移植時，大多數中心都要求腫瘤情況應符合米蘭標準[143-144, 147-148, 151]。但也有些中心采用擴展標準，如京都大學標準[152]、九州大學標準[145]、杭州標準[149]、up-to-7 標準[150]。許多研究[143, 145, 152]亦證實，對于 RHCC 患者，活體肝移植是安全有效的。但目前尚缺乏針對 RHCC 患者的尸體肝移植和活體肝移植預后比較的報道。
推薦 9：RHCC 患者能夠從肝移植中生存獲益，但腫瘤需符合特定的移植標準。行挽救性肝移植時，活體肝移植同樣是安全有效的（證據等級Ⅱa；推薦意見級別 B）
7.4 可切除性 RHCC 伴門靜脈癌栓的手術適應證
HCC 合并門靜脈癌栓是否應接受手術切除一直存在較大爭議。近年來，有較多文獻報道此類患者中有部分患者可從手術中獲益。亞太地區學者[49, 153-154]認為，對于部分 HCC 合并門靜脈癌栓的患者應考慮手術切除，但應重視患者的篩選。對于 RHCC 伴門靜脈癌栓患者，更應嚴格把握此類患者手術切除的適應證。首次，根治性切除術后復發時間大于 1 年，為可切除性復發腫瘤，估計癌栓形成的時間比較短尚未發生機化，門靜脈癌栓分型屬于Ⅰ、Ⅱ或Ⅲ型，適合肝段、肝葉等解剖性肝切除，可考慮行肝葉、半肝等解剖性肝切除術加門靜脈取栓術[24]。但 HCC 合并Ⅲ型門靜脈癌栓患者的預后更差，應慎重選擇[155]。
推薦 10：對于肝內 RHCC 伴門靜脈癌栓患者，在綜合評估、嚴格掌握指征的基礎上仍可考慮手術治療（證據等級Ⅲ；推薦意見級別 B）
7.5 可切除性 RHCC 伴膽管癌栓的手術適應證
對初次手術切除 HCC 不伴 MVI 等復發高危因素、復發時間在 1 年以上的 HCC 肝內復發伴膽管癌栓的患者，原則上應爭取外科手術完整切除腫瘤及取盡癌栓，特別是對那些不伴梗阻性黃疸的患者[156-159]。對腫瘤個數小于 3 個，局限在肝段或肝葉，預估有足夠的殘余肝體積，癌栓位于腫瘤側膽管者，可行腫瘤及癌栓累及膽管的解剖性肝切除。對 RHCC 可切除，癌栓進入膽總管，癌栓形成時間較短尚未發生機化者，可行肝葉、半肝等的解剖性肝切除術加膽管探查癌栓取出術加 T 管引流術[158, 160-161]；對癌栓形成時間長，但癌栓局限在肝外膽管，RHCC 可切除者，可考慮行肝切除術加肝外膽管切除術加膽腸吻合術[11, 156]。
推薦 11：初次 HCC 不合并 MVI 等復發高危因素，RHCC 可切除，癌栓位于腫瘤側膽管，推薦行解剖性肝切除術。對于合并膽總管癌栓患者，應謹慎選擇外科手術（證據等級Ⅲ；推薦意見級別 B）。
7.6 可切除性 RHCC 伴腔靜脈癌栓的手術適應證
手術切除腫瘤和取盡腔靜脈癌栓、降低栓子脫落導致突發死亡的風險，是目前唯一可能治愈 RHCC 合并腔靜脈癌栓患者的手段[162-163]。對腫瘤個數小于 3 個，局限在肝段或肝葉，術前評估有足夠的肝體積，癌栓未延伸至心房，腔靜脈癌栓形成時間較短尚未發生機化者[162]，可行肝切除加全肝血流隔離下取盡腔靜脈癌栓；如癌栓延伸到右心房，應在體外循環下取盡心房及腔靜脈的癌栓[164]。RHCC 伴腔靜脈癌栓手術風險高，預后不確定，指征宜從嚴掌握。初次 HCC 切除 2 年以上，不伴 MVI 等高危復發因素，術前對 TACE 反應良好者更適合接受這類手術[165]。
推薦 12：可切除性 RHCC 合并腔靜脈癌栓患者，特別是復發癌對 TACE 反應良好者，推薦 HCC 切除加癌栓取出術（證據等級Ⅲ；推薦意見級別 B）。同時合并門靜脈癌栓者不建議手術治療（證據等級Ⅲ；推薦意見級別 B）
7.7 可切除性 RHCC 伴肝硬化、門靜脈高壓癥、脾大脾功能亢進聯合脾切除術適應證
肝內 RHCC 具可切除性，伴中、重度脾腫大，重度脾功能亢進（WBC <3×109/L，PLT<50×109/L）表現者，應考慮行 HCC 切除聯合脾切除術[166-171]。對有明顯食管胃底靜脈曲張，特別是發生過食管胃底曲張靜脈破裂大出血的患者，經過嚴格的評估后還應同時行賁門周圍血管離斷術。對有嚴重胃黏膜病變患者，如果患者術中情況允許，應行脾腎分流術或其他類型的選擇性門腔分流術。此類患者都應考慮將來行肝移植的可能性，故應慎行斷流術或分流術。此類聯合手術宜從嚴掌握，如患者有既往肝功能不全、凝血功能障礙等病史，應考慮行挽救性肝移植。
推薦 13：肝內 RHCC 伴肝硬化門靜脈高壓癥中、重度脾大脾功能亢進可聯合脾切除術，但應嚴格評估患者的肝功能、肝儲備功能（證據等級Ⅳ；推薦意見級別 B）
8 RHCC 的介入治療
以往的 RCT 研究結果[172-173]顯示，病灶局限在肝內而且沒有血管侵襲的 HCC 患者可以從 TACE 治療中獲益。TACE 雖然不是治療 HCC 的根治性手段，但有約 10% 的 HCC 患者在接受序貫 TACE 治療后獲得完全緩解[174]。對于 RHCC 病灶數目≤3 個，腫瘤直徑≤5 cm 的患者，TACE 和 RFA 的效果相當[175]，尤其是對于切除或移植術后有多處肝內復發的患者，TACE 是降低復發后死亡率的重要手段[176]。還有研究結果[95]顯示，符合米蘭標準的 RHCC，早期復發時 TACE 和 RFA/切除具有相同的效果；后期復發時， RFA/切除效果好于 TACE。Jin 等[177]比較了 TACE、切除和 RFA 治療對伴有 MVI 的 RHCC 的治療效果，結果顯示， TACE 治療 MVI 陽性的 RHCC 患者可以獲得較切除和 RFA 治療更好的 OS 和 DFS，特別是對于 1 年內復發的 MVI 陽性患者，OS 顯著高于切除組和 RFA 組。Yang 等[178]回顧性研究了 TACE 聯合 RFA 與單獨行 TACE 或 RFA 治療 RHCC 的效果，聯合治療組患者的治療成功率和 5 年生存率都顯著高于單獨 TACE 組或 RFA 組。因此，TACE 治療的指征有[122,179]：①RHCC 病灶臨近重要血管或膽管而無法行切除或 RFA 治療；② 肝內多發復發腫瘤；③ 早期肝內 RHCC（1 年內）；④ 患者個人選擇 TACE 治療。
推薦 14：對于早期肝內 RHCC（肝切除術后 1 年內）、病灶臨近重要血管或膽管而無法行切除或消融治療的 RHCC、肝內多個 RHCC 病灶，TACE 可控制 HCC 進展，帶來生存獲益（證據等級Ⅱa；推薦意見級別 A）
9 RHCC 的放射治療
放療是治療 RHCC 有效和安全的手段之一[180-181]，國內外研究報道，小肝癌行放療 5 年生存率可達 60% 以上[182-183]，甚至療效等同于 RFA 治療[184]，但與手術相比尚無直接證據。RHCC 患者常面臨腫瘤位于切除困難位置、巨大、多發、大血管癌栓形成及肝功能失代償等因素，也常伴發肺、骨等部位的肝外轉移，對此可根據腫瘤的情況選擇合適的放療方式，可多次實施以縮小肝內外病灶，控制腫瘤進展，減輕腫瘤引起的癥狀，延長患者生存時間。如肺轉移患者經體外放射治療其 2 年生存率可達 70.7%，骨轉移患者經體外放射治療其中位生存期達到 7.4 個月[185-191]。對于 HCC 肝移植術后復發患者，可有效控制復發癌的進展。放療也可聯合介入治療改善晚期 RHCC 患者的預后[192]。
HCC 患者接受 TACE 聯合阿霉素載藥緩釋微球[193]和放射微球[194]治療能獲得更高的腫瘤壞死率和更低的腫瘤進展率。但其在 RHCC 中的作用尚待研究。
推薦 15：復發性小肝癌且不宜手術切除者，可選擇放射治療（證據等級Ⅱb，推薦意見級別 B）；RHCC 合并肝外轉移者也可選擇放射治療（證據等級Ⅲ；推薦意見級別 B）
10 HCC 切除術后復發的全身治療[3 ]
10.1 抗病毒治療
TACE、手術和化療均可引起乙型肝炎病毒復燃，而且抗病毒治療可以降低 TACE 及手術之后的復發率，改善患者的生存。因此，對合并有乙肝病毒感染且復制活躍的 HCC 患者，推薦口服核苷（酸）類似物抗病毒治療[58, 60]。
10.2 抗腫瘤治療
10.2.1 分子靶向藥物 索拉非尼是國際公認的治療晚期 HCC 的分子靶向藥物。兩項大型國際多中心Ⅲ期臨床試驗均證明了索拉非尼對于不同國家地區、不同肝病背景的晚期 HCC 具有一定的生存獲益[70]。近來，瑞戈非尼已獲批成為晚期 HCC 的二線分子靶向藥物。
10.2.2 系統化療 奧沙利鉑在我國被批準用于治療不適合手術切除或局部治療的 HCC[195]。適應證主要為：① 合并有肝外轉移的晚期患者；② 雖為局部病變，但不適合手術治療和 TACE 者；③ 合并門靜脈主干或下腔靜脈瘤栓者；④ 多次 TACE 后血管阻塞和（或）TACE 治療后復發的患者。
10.2.3 免疫治療 HCC 的免疫治療主要包括免疫調節劑（胸腺肽 α1、干擾素 α 等）[62, 196]、免疫檢查點阻斷劑（CTLA-4 阻斷劑、PD-1/PD-L1 阻斷劑等）、腫瘤疫苗（樹突細胞疫苗等）和細胞免疫治療[197]。這些治療手段均有一定的抗腫瘤作用，但尚待大規模的臨床研究驗證。
10.2.4 中醫中藥 中醫中藥治療能夠改善癥狀，提高機體的抵抗力，減輕放化療的不良反應，提高生活質量。但缺乏高級別的循證醫學證據。
10.3 對癥支持治療
適度的康復運動、積極鎮痛、改善睡眠、增加營養、心理治療等對癥支持治療可增強機體的免疫功能，改善患者的生活質量和預后。
11 HCC 切除術后復發的綜合治療
目前在中國，HCC 診治領域的特點仍然是多方法、多學科共存，而以治療手段建科的分科診療體制與實現有序規范的 HCC 治療之間存在一定的矛盾[3]。因此，HCC 的 MDT 下的合理規范的治療方法選擇與綜合治療就顯得極其重要，特別是對 RHCC 的治療。已進行抗病毒治療的 HCC 切除術后伴有復發高危風險患者，聯合 TACE、索拉非尼與胸腺肽 α1 治療，還有肝內 RHCC 的 RFA 聯合 TACE 治療[178]等，都是綜合治療的典范，能讓患者更好的生存獲益。
12 展望
首先我們承認，本初始版本的共識，很多研究的循證醫學證據級別較低，但為了及時反映我國學者在 HCC 切除術后復發防治方面所做的不懈努力而取得的成果，有必要制訂適合我國國情的規范化方案，用于我們在處理 HCC 切除術后復發防治的患者時的參考。同時，新的循證醫學證據還在不斷涌現和補充，與 HCC 切除術后復發防治相關的很多隨機對照研究正在進行中，我們期望逐步完善該方面的共識。
為了進一步做好相關的研究及完善共識，在臨床實踐中應重視以下幾點原則：① MDT 是 HCC 診治的必然工作方式，通過積極有效的多學科綜合診治，HCC 切除術后復發的防治必將取得較大進展，從而改善 HCC 患者的總體預后。② HCC 切除術后復發為根治帶來巨大障礙，患者帶瘤生存時間和總體生存時間會作為療效評價的重要指標，我們讓患者在帶瘤生存的同時應努力提高他們的生命質量。③ 我國 HCC 切除術后復發患者多，病情復雜，通過開展更多的隨機對照研究來開發、驗證更多有效的 RHCC 的診斷與治療方法，并建立 RHCC 生物樣本庫，加強對 HCC 復發轉移的發生發展內在相關分子機制的研究，特別是 HCC 的分子分型、靶向治療和相關的轉化醫學的探索，將為精準治療提供更多證據，推動我國 HCC 防治事業的發展。
《肝細胞癌切除術后復發轉移的防治：華西醫院多學科專家共識》編審成員名單：
名譽組長：嚴律南
組 長：文天夫
成 員（以姓氏拼音為序）：
曹丹1，陳恩強2，陳衛霞3，陳哲宇4，黃紀偉4，蔣利4，李波4，李秋1，李志平1，魯昌立5，盧強6，盧武勝4，羅燕6，唐紅2，王文濤4，王辛1，魏永剛4，吳苾3，吳泓4，徐明清4，楊家印4，曾勇4，張鳴4（1：腫瘤中心；2：感染性疾病中心；3：放射科；4：肝臟外科；5：病理科；6：超聲診斷科）
編寫秘書：李川、劉暢、彭偉、張曉赟、彭馳涵、沈俊頤、金諶
表1 證據等級
| 證據級別 | 描述 |
| Ⅰa | 證據源于對多項隨機對照研究的 meta 分析結果 |
| Ⅰb | 證據源于至少一項設計良好的隨機對照研究結果 |
| Ⅱa | 證據源于至少一項設計良好的前瞻性非隨機對照研究結果 |
| Ⅱb | 證據源自至少一項設計良好的其他類型干預性臨床研究結果 |
| Ⅲ | 證據源于設計良好的非干預性研究，如描述性研究、相關性研究等 |
| Ⅳ | 證據源于專家委員會報告或權威專家的臨床經驗報道 |
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表2 推薦意見級別
| 證據等級 | 描述 |
| A | 良好的科學證據提示該醫療行為帶來明確獲益，建議醫師對患者實施該醫療行為 |
| B | 現有證據表明該醫療行為可帶來中度獲益，超過其潛在風險；醫師可建議對患者實施該醫療行為 |
| C | 現有證據表明該醫療行為可能獲益較小，或獲益與風險接近；醫師可根據患者個體情況有選擇地向患者建議或實施該醫療行為 |
| D | 現有證據表明該醫療行為無獲益，或其潛在風險超過獲益；醫師不宜向患者實施該醫療行為 |
| E | 缺乏科學證據，或現有證據無法評價該醫療行為的獲益與風險；醫師應幫助患者理解該醫療行為存在的不確定性 |
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