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通讯作者:

李江涛(1970-),男,内蒙古人,博士生导师,主要从事肝胆胰外科基础和临床研究。E-mail:zjulijiangtao@163.com

中图分类号:R593.22

文献标识码:A

文章编号:2096-8965(2020)01-0026-09

DOI:10.12287/j.issn.2096-8965.20200105

参考文献 1
BANALES J M,CARDINALE V,CARPINO G,et al.Cholangiocarcinoma:current knowledge and future perspectives consensus statement from the european network for the study of cholangiocarcinoma(ENS-CCA)[J].Nat Rev Gastroenterol Hepatol,2016,13(5):261-80.
参考文献 2
吴锦洪,李江涛.肝内胆管细胞癌的淋巴结清扫:共识和争议[J].肝胆外科杂志,2016,24(5):321-323.
参考文献 3
BERTUCCIO P,MALVEZZI M,CARIOLI G,et al.Global trends in mortality from intrahepatic and extrahepatic cholangiocarcinoma[J].J Hepatol,2019,71(1):104-114.
参考文献 4
ZHOU Z,NIE S D,JIANG B,et al.Risk factors for extrahepatic cholangiocarcinoma:a case-control study in China[J].European Journal of Cancer Prevention,2019,28(4):254-257.
参考文献 5
VAN VUGT J L A,GASPERSZ M P,COELEN R J S,et al.The prognostic value of portal vein and hepatic artery involvement in patients with perihilar cholangiocarcinoma[J].HPB(Oxford),2018,20(1):83-92.
参考文献 6
GROOT KOERKAMP B,WIGGERS J K,ALLEN P J,et al.Recurrence rate and pattern of perihilar cholangiocarcinoma after curative intent resection[J].J Am Coll Surg,2015,221(6):1041-1049.
参考文献 7
SPOLVERATO G,KIM Y,ALEXANDRESCU S,et al.Management and outcomes of patients with recurrent intrahepatic cholangiocarcinoma following previous curativeintent surgical resection[J].Ann Surg Oncol,2016,23(1):235-243.
参考文献 8
SIRICA A E,GORES G J,GROOPMAN J D,et al.Intrahepatic cholangiocarcinoma:continuing challenges and translational advances[J].Hepatology,2019,69(4):1803-1815.
参考文献 9
BISMUTH H,ADAM R,LEVI F,et al.Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy[J].Ann Surg,1996,224(4):509-520,discussion 20-22.
参考文献 10
江杰,胡宗强,陈刚,等.原发性肝癌转化治疗研究进展[J].临床肝胆病杂志,2020,36(8):1870-1873.
参考文献 11
何霞飞,周永宁,关泉林.Ⅳ期胃癌转化治疗现状[J].肿瘤药学,2020,10(2):139-147,165.
参考文献 12
WANG T,WANG N,REN H,et al.Long-term results of conversion therapy for initially unresectable gastric cancer:analysis of 122 patients at the National Cancer Center in China[J].Journal of Cancer,2019,10(24):5975-5985.
参考文献 13
RIBY D,MAZZOTTA A D,BERGEAT D,et al.Downstaging with radioembolization or chemotherapy for initially unresectable intrahepatic cholangiocarcinoma[J].Ann Surg Oncol,2020,27:3729-3737.
参考文献 14
LE ROY B,GELLI M,PITTAU G,et al.Neoadjuvant chemotherapy for initially unresectable intrahepatic cholangiocarcinoma[J].Br J Surg,2018,105(7):839-47.
参考文献 15
CHO Y,KIM T H,SEONG J.Improved oncologic out-come with chemoradiotherapy followed by surgery in unresectable intrahepatic cholangiocarcinoma[J].Strahlentherapie und Onkologie,2017,193(8):620-629.
参考文献 16
ULUSAKARYA A,KARABOUE A,CIACIO O,et al.A retrospective study of patient-tailored FOLFIRINOX as a first-line chemotherapy for patients with advanced biliary tract cancer[J].BMC Cancer,2020,20(1):515.
参考文献 17
SHROFF R T,JAVLE M M,XIAO L,et al.Gemcitabine,cisplatin,and nab-paclitaxel for the treatment of advanced biliary tract cancers:a phase 2 clinical trial[J].JAMA Oncol,2019,5(6):824-830.
参考文献 18
SHAO F,QI W,MENG F T,et al.Role of palliative radiotherapy in unresectable intrahepatic cholangiocarcinoma:population-based analysis with propensity score matching[J].Cancer Management and Research,2018,10:1497-1506.
参考文献 19
SUMIYOSHI T,SHIMA Y,OKABAYASHI T,et al.Chemoradiotherapy for initially unresectable locally advanced cholangiocarcinoma[J].World J Surg,2018,42(9):2910-2918.
参考文献 20
VERMA V,KUSI APPIAH A,LAUTENSCHLAEGER T,et al.Chemoradiotherapy versus chemotherapy alone for unresected intrahepatic cholangiocarcinoma:practice patterns and outcomes from the national cancer data base[J].Journal of Gastrointestinal Oncology,2018,9(3):527-535.
参考文献 21
BURGER I,HONG K,SCHULICK R,et al.Transcatheter arterial chemoembolization in unresectable cholangiocarcinoma:initial experience in a single institution[J].J Vasc Interv Radiol,2005,16(3):353-561.
参考文献 22
PARK S Y,KIM J H,YOON H J,et al.Transarterial chemoembolization versus supportive therapy in the palliative treatment of unresectable intrahepatic cholangiocarcinoma[J].Clin Radiol,2011,66(4):322-328.
参考文献 23
KIM J H,YOON H K,SUNG K B,et al.Transcatheter arterial chemoembolization or chemoinfusion for unresectable intrahepatic cholangiocarcinoma:clinical efficacy and factors influencing outcomes[J].Cancer,2008,113(7):1614-1622.
参考文献 24
HERBER S,OTTO G,SCHNEIDER J,et al.Transarterial chemoembolization(TACE)for inoperable intrahepatic cholangiocarcinoma[J].Cardiovasc Intervent Radiol,2007,30(6):1156-1165.
参考文献 25
VOGL T J,NAGUIB N N,NOUR-ELDIN N E,et al.Transarterial chemoembolization in the treatment of patients with unresectable cholangiocarcinoma:results and prognostic factors governing treatment success[J].Int J Cancer,2012,131(3):733-740.
参考文献 26
ZHOU T Y,ZHOU G H,ZHANG Y L,et al.Drug-eluting beads transarterial chemoembolization with CalliSpheres microspheres for treatment of unresectable intrahepatic cholangiocarcinoma[J].Journal of Cancer,2020,11(15):4534-4541.
参考文献 27
KUHLMANN J B,EURINGER W,SPANGENBERG H C,et al.Treatment of unresectable cholangiocarcinoma:conventional transarterial chemoembolization compared with drug eluting bead-transarterial chemoembolization and systemic chemotherapy[J].Eur J Gastroenterol Hepatol,2012,24(4):437-443.
参考文献 28
AL-ADRA D P,GILL R S,AXFORD S J,et al.Treatment of unresectable intrahepatic cholangiocarcinoma with yttrium-90 radioembolization:a systematic review and pooled analysis[J].Eur J Surg Oncol,2015,41(1):120-127.
参考文献 29
AKINWANDE O,SHAH V,MILLS A,et al.Chemoembolization versus radioembolization for the treatment of unresectable intrahepatic cholangiocarcinoma in a single institution image-based efficacy and comparative toxic-ity[J].Hepatic Oncology,2017,4(3):75-81.
参考文献 30
BUETTNER S,BRAAT A,MARGONIS GA,et al.Yttrium-90 radioembolization in intrahepatic cholangiocarcinoma:a multicenter retrospective analysis[J].J Vasc Interv Radiol,2020,31(7):1035-1043.
参考文献 31
WANG L,KE Q,LIN N,et al.The efficacy of transarterial chemoembolization combined with microwave ablation for unresectable hepatocellular carcinoma:a systematic review and meta-analysis[J].International Journal of Hyperthermia,2019,36(1):1288-1296.
参考文献 32
WU L,TSILIMIGRAS D I,FAROOQ A,et al.Potential survival benefit of radiofrequency ablation for small solitary intrahepatic cholangiocarcinoma in nonsurgically managed patients:a population-based analysis[J].J Surg Oncol,2019,120(8):1358-1364.
参考文献 33
BRANDI G,RIZZO A,DALL'OLIO F G,et al.Percutaneous radiofrequency ablation in intrahepatic cholangiocarcinoma:a retrospective single-center experience[J].International Journal of Hyperthermia,2020,37(1):479-485.
参考文献 34
MASSIRONI S,PILLA L,ELVEVI A,et al.New and emerging systemic therapeutic options for advanced cholangiocarcinoma[J].Cells,2020,9(3):688.
参考文献 35
LOUIS C,PAPOUTSOGLOU P,COULOUARN C.Molecular classification of cholangiocarcinoma[J].Curr Opin Gastroenterol,2020,36(2):57-62.
参考文献 36
JAVLE M,LOWERY M,SHROFF R T,et al.Phase Ⅱstudy of BGJ398 in patients with FGFR-altered advancedcholangiocarcinoma[J].J Clin Oncol,2018,36(3):276-282.
参考文献 37
MAZZAFERRO V,EL-RAYES B F,DROZ DIT BUSSET M,et al.Derazantinib(ARQ 087)in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma[J].Br J Cancer,2019,120(2):165-171.
参考文献 38
ABOU-ALFA G K,SAHAI V,HOLLEBECQUE A,et al.Pemigatinib for previously treated,locally advanced or metastatic cholangiocarcinoma:a multicentre,open-label,phase 2 study[J].Lancet Oncol,2020,21(5):671-684.
参考文献 39
GOYAL L,SHI L,LIU L Y,et al.TAS-120 overcomes resistance to ATP-competitive FGFR inhibitors in patients with FGFR2 fusion-positive intrahepatic cholangiocarcinoma[J].Cancer Discovery,2019,9(8):1064-1079.
参考文献 40
BORGER D R,TANABE K K,FAN K C,et al.Frequent mutation of isocitrate dehydrogenase(IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping[J].Oncologist,2012,17(1):72-79.
参考文献 41
LOWERY M A,BURRIS H A,JANKU F,et al.Safety and activity of ivosidenib in patients with IDH1-mutant advanced cholangiocarcinoma:a phase 1 study[J].The Lancet Gastroenterology & Hepatology,2019,4(9):711-720.
参考文献 42
ABOU-ALFA G K,MACARULLA T,JAVLE M M,et al.Ivosidenib in IDH1-mutant,chemotherapy-refractory cholangiocarcinoma(ClarIDHy):a multicentre,randomised,double-blind,placebo-controlled,phase 3 study[J].Lancet Oncol,2020,21(6):796-807.
参考文献 43
GALDY S,LAMARCA A,MCNAMARA M G,et al.HER2/HER3 pathway in biliary tract malignancies;systematic review and meta-analysis:a potential therapeutic target?[J].Cancer Metastasis Reviews,2017,36(1):141-157.
参考文献 44
RIZZO A,FREGA G,RICCI A D,et al.Anti-EGFR monoclonal antibodies in advanced biliary tract cancer:a systematic review and meta-analysis[J].In Vivo,2020,34(2):479-488.
参考文献 45
GOYAL L,ZHENG H,YURGELUN M B,et al.A phase 2 and biomarker study of cabozantinib in patients with advanced cholangiocarcinoma[J].Cancer,2017,123(11):1979-1988.
参考文献 46
LEE S H,LEE H S,LEE S H,et al.Efficacy and safety of pembrolizumab for gemcitabine/cisplatin-refractory biliary tract cancer:a multicenter retrospective study[J].Journal of Clinical Medicine,2020,9(6):1769.
参考文献 47
KANG J,JEONG J H,HWANG H S,et al.Efficacy and safety of pembrolizumab in patients with refractory advanced biliary tract cancer:tumor proportion score as a potential biomarker for response[J].Cancer Research and Treatment,2020,52(2):594-603.
参考文献 48
GOU M,ZHANG Y,SI H,et al.Efficacy and safety of nivolumab for metastatic biliary tract cancer[J].OncoTargets and Therapy,2019,12:861-867.
参考文献 49
UENO M,IKEDA M,MORIZANE C,et al.Nivolumab alone or in combination with cisplatin plus gemcitabine in Japanese patients with unresectable or recurrent biliary tract cancer:a non-randomised,multicentre,open-label,phase 1 study[J].The Lancet Gastroenterology & Hepatology,2019,4(8):611-621.
参考文献 50
KIM R D,CHUNG V,ALESE O B,et al.A Phase 2 multi-institutional study of nivolumab for patients with advanced refractory biliary tract cancer [J].JAMA Oncol,2020,6(6):888-894.
参考文献 51
SHEN L,GUO J,ZHANG Q,et al.Tislelizumab in Chinese patients with advanced solid tumors:an open-label,non-comparative,phase 1/2 study[J].Journal for Immunotherapy of Cancer,2020,8(1):e000437.
参考文献 52
DESAI J,DEVA S,LEE J S,et al.Phase IA/IB study of single-agent tislelizumab,an investigational anti-PD-1 antibody,in solid tumors[J].Journal for Immunotherapy of Cancer,2020,8(1):e000453.
参考文献 53
MOSER J C,PULIDO J S,DRONCA R S,et al.The Mayo Clinic experience with the use of kinase inhibitors,ipilimumab,bevacizumab,and local therapies in the treatment of metastatic uveal melanoma[J].Melanoma Research,2015,25(1):59-63.
参考文献 54
LIANG T Z,WHANG G,CHOPRA S.Primary hepatic carcinoma with inhibin positivity in a young male patient:a rare tumor previously only reported in females-case report and review of literature[J].Virchows Archiv,2020.
参考文献 55
INOZUME T,HANADA K,WANG Q J,et al.IL-17 secreted by tumor reactive T cells induces IL-8 release by human renal cancer cells[J].Journal of Immunotherapy,2009,32(2):109-117.
参考文献 56
KLEIN O,KEE D,NAGRIAL A,et al.Evaluation of combination nivolumab and ipilimumab immunotherapy in patients with advanced biliary tract cancers:subgroup analysis of a phase 2 nonrandomized clinical trial[J].JAMA Oncol,2020,6(9):1405-1409.
参考文献 57
吴锦洪,周冬儿,于源泉,等.肝内胆管癌新辅助化疗后手术切除1例报告并文献复习[J].中国实用外科杂志,2017,37(7):818-820,822.
参考文献 58
彭淑牖,王许安,黄从云,等.以实际解剖部位命名的分型法:对五种胆道疾病分型的思考[J].中华外科杂志,2019,57(6):412-417.
目录contents

    摘要

    肝内胆管癌是仅次于肝细胞肝癌最常见的肝脏恶性肿瘤之一,在我国肝内胆管癌的发病率处于较高水平。目前,肝内胆管癌的治疗仍以手术切除为主,但由于肝内胆管癌在早期多无特异性症状,患者常在确诊时即为晚期,失去手术机会。转化治疗是近些年被提出的新概念,其认为初始无法手术切除的恶性肿瘤可以通过多种治疗方式进行降期,从而使患者得到手术的机会,延长患者的生存时间。随着各种新型抗肿瘤药物的研发以及疗效的验证,肝内胆管癌的转化治疗也迎来了曙光。本文即围绕肝内胆管癌转化治疗的现状以及本团队在该领域的实践经验这两个方面进行阐述。

    Abstract

    Intrahepatic cholangiocarcinoma (ICC) is one of the most common malignant liver tumors after hepatocellular carcinoma, the incidence rate of which in our country is rather high. At present, surgical resection is still main treatment for ICC. However, due to the lack of specific symptoms at early stage, ICC patients are often diagnosed at late stage and loss of the opportunity of surgical treatments. Conversion therapy is a novel concept proposed recently. It demonstrated that malignant tumors that cannot be resected initially can be downsized by various treatments, so that patients obtained the chance of surgical treatments and get prolonged survival time. With the development of novel anti-tumor drugs, conversion therapy of ICC also is in the first flush of dawn. This review summarizes the current situation of ICC conversion therapy and our practical experience.

  • 肝内胆管癌(Intrahepatic Cholangiocarcinoma, ICC) 是仅次于肝细胞肝癌最常见的肝脏恶性肿瘤之一,约占所有肝脏原发性肿瘤的15%[1]。其来源于肝内二级胆管及其分支的胆管内皮细胞,病理类型可分为腺癌、腺鳞癌、鳞癌、黏液癌和印戒细胞癌等,其中以腺癌最为多见。根据肿瘤生长类型分为肿块型、管周浸润型、管内生长型三类[2]。目前ICC发病的危险因素尚不十分明确,胆道结石、胆道感染、肝硬化、原发性硬化性胆管炎、某些化学物质或药物均有可能诱导ICC的发生[3, 4]。我国ICC的发病率在国际上属于较高水平,据报道,我国ICC的发病率约为(7.45~7.55)/10 万[1],这需要引起社会的重视。

  • ICC的治疗方案目前仍以手术切除为主,并辅以术后辅助治疗[2]。但由于ICC在早期多无特异性症状,患者常因黄疸、腹痛、腹部肿块等原因就诊时才发现ICC,此时肿瘤多已进展,失去手术机会,根治性手术切除率不足10%[5]。另一方面,即使进行了手术切除,ICC较高的术后复发率也使得患者的预后较差,根据报道,ICC患者术后5年的生存率仅为7%~20%[6-8]。因此,ICC目前的治疗主要是以手术为主的综合治疗模式。NCCN的指南中治疗决策路径分为可切除型、不可切除型、转移型三类,三类病人中后两类往往发现时初始不能切除,提高手术切除率仍是该疾病亟需提高的方向。

  • 转化治疗(Conversion Therapy)的概念在1996 年被法国学者Bismuth提出,其认为初始无法手术切除的结直肠癌肝转移患者可以通过全身化疗以进行降期,从而使患者得到手术的机会,延长患者的生存时间[9]。后来这一概念在其他肿瘤治疗领域普及,现已广泛应用于胃癌、肝细胞肝癌等的治疗中,并取得了一定的效果[10-12]。ICC转化治疗的概念应用较少,近年来,随着药物研发的进步,部分药物对ICC显现出了较好的疗效,为ICC的转化治疗创造了可能性。本文就ICC转化治疗的适应症、 转化治疗的方法、以及本团队的实践经验进行总结。

  • 1 ICC转化治疗的适应症

  • 目前我们治疗中遵循的指南一般为美国国立综合癌症网络(National Comprehensive Cancer Network,NCCN) 指南,按照TNM分期,T1 期分为T1a(肿瘤≤5 cm) 或T1b(肿瘤>5 cm) 无血管侵犯,T2 期孤立的肝内肿瘤合并血管侵犯或多发肿瘤伴或不伴血管侵犯。T3期为肿瘤突破脏层腹膜。 T4 期为直接侵犯肝外结构。因此根据我们转化治疗的成功经验,结合T分期,T2和T3期病人和部分T1b病人可以考虑为ICC的转化治疗候选者。

  • 此外,考虑到ICC早期易发生淋巴结转移,是引起预后不良的主要因素,因此如术前考虑淋巴结转移也可以考虑为ICC转化治疗的适应症。

  • 转化治疗在ICC中的应用既包括对最初没有手术指征的肿瘤进行多种系统或局部治疗,使其满足手术切除可能以进行R0 切除,也包括对存在手术指征但存在血管侵犯或广泛淋巴结转移的肿瘤进行术前辅助治疗,以达到肿瘤从不可切除转化为可切除的目的。

  • 2 转化治疗的方法

  • 2.1 系统化疗

  • 系统化疗是目前ICC最常用的治疗方式,其中吉西他滨联合铂类药物的方案是NCCN指南推荐的进展期ICC的一线化疗方案,除此之外,5-氟尿嘧啶联合铂类,吉西他滨联合卡培他滨,吉西他滨联合白蛋白紫杉醇、吉西他滨联合5-氟尿嘧啶等治疗方案也可作为ICC的转化治疗方法。

  • Riby等的研究发现,初始没有手术指征的ICC患者,在经过基于吉西他滨的化疗方案转化治疗后,行根治性手术,可以获得与初始即存在手术指征的患者相似的生存时间[13]。在一项法国的前瞻性单中心研究中,74名局部进展期ICC患者接受了系统化疗,其中有39 名患者转化成功并接受了根治性切除手术,这些患者的预后与初始即存在手术指征的患者相似[14]。在Cho等的研究中,64名进展期患者接受了以吉西他滨为主的系统化疗以期对肿瘤进行降期,结果16名患者可得到部分缓解(Partial Response,PR),其中8 名患者后续接受了根治性切除,这些患者的预后相较于降期失败的患者有着显著的改善[15]。另有一项研究使用奥沙利铂、伊立替康、氟尿嘧啶、亚叶酸钙联合方案(FOLFIRINOX方案) 作为一线用药,用于治疗进展期的胆管癌。该研究纳入了42 名胆管癌患者,其中ICC患者21名(50%),最终在使用了FOLFIRINOX方案系统化疗降期后,有6名患者满足了手术指征并接受了R0 或R1 的后续手术,3 年生存率达到了83%[16]

  • 目前来看,转化成功的ICC患者可以获得较为满意的预后。但单纯使用系统化疗进行肿瘤转化的效率较低,多数患者无法取得理想的降期效果。联合更多化疗药物可能是一种途径,Shroff等的研究联合了吉西他滨、顺铂、白蛋白紫杉醇对进展期胆管癌进行治疗,结果显示,在总共60 名患者中, 肿瘤总体的部分缓解率可达到45%,但这一方案也带来了严重的不良反应,有9名患者因为严重不良反应退出了研究[17]。这项研究提示联合多种化疗药物固然可以提高肿瘤缓解率,但同时也会带来诸多不良反应,因此提高转化治疗的效率可能还是需要联合其他治疗方式来实现。

  • 2.2 放射治疗

  • 放射治疗在转化治疗中常常是与系统化疗联用的。在单独使用放射治疗时,ICC患者虽然可以取得比不接受任何治疗的患者更好的预后,但是由于治疗的位置较为局限,很难使肿瘤降期达到手术要求,更多是作为姑息性治疗方式的一种[18]。而Sumiyoshi等的研究发现,放疗与系统化疗联用时, 可以有效地对不可切除的胆管癌进行降期,他们的研究中11名患者(73.3%) 降期成功并接受了手术切除治疗,最终5年生存率达到了23.6%[19]。Verma等的研究也发现,与单独使用系统化疗相比,放化疗联合使用可以使ICC患者总体生存时间从10.5个月延长至13.6个月[20]

  • 2.3 介入治疗

  • 2.3.1 经肝动脉化疗栓塞(Transarterial ChemoemBolization,TACE)

  • TACE用于ICC的治疗已有数十年的历史,对于初始不存在手术指征的ICC患者,TACE可以有效延长患者的生存时间,改善患者预后,并且有一定可能将肿瘤转化降期,进行手术切除。早在2005 年Burger等的研究就发现,其研究的17 名不可切除ICC患者在使用TACE治疗后,有2 名患者(11.8%) 具备了手术指征,并进行了手术切除,所有患者的平均总体生存时间可达到23 个月[21]。随后的研究也验证了这一结论,TACE对于不可切除的ICC有着较好的疗效,且不良反应小,但对于存在血管侵犯的肿瘤效果欠佳[22-25]。近年来,新型的载药微球(Drug-elutingbeads,DEB) TACE应用广泛,其进行传统TACE操作的同时向肿瘤注射DEB,这些微球可以持续可控地释放抗肿瘤药物。 一项研究指出,88 名不可切除ICC患者接受DEBTACE治疗后,58名患者(65.9%) 病情获得了PR, 19名患者(21.6%)病情稳定(Stable Disease,SD), 11名患者(12.5%) 病情进展(Progressive Disease, PD),主要的不良反应为恶心呕吐和腹痛[26]。与传统TACE相比,DEB-TACE在控制局部病灶进展和延长患者生存时间方面均具有显著优势,但对血管侵犯的肿瘤效果仍比较差[27]

  • 2.3.2 经肝动脉放疗栓塞(Transarterial Radioembolization,TARE)

  • TARE是另一种经肝动脉的介入治疗方法,目前最常用的放射物质是Y90微球,其有别于传统放疗,通过定点释放放疗物质的方式,减少了放射剂量,减少了对正常细胞的杀伤,同时定点的释放提高了放疗的效果。多项研究均显示TARE用于治疗不存在手术指征的ICC患者时疗效与传统化疗或TACE相当[28, 29]。一项多中心回顾性研究显示,在115 名接受了TARE治疗的进展期ICC患者中,有5名患者(4%)实现了转化降期,接受了根治性手术[30]。 与TACE类似的是,主要影响TARE疗效的因素也是肿瘤的大小和血管的侵犯,肿瘤侵犯的范围越广,患者的预后也就越差。

  • 2.4 局部消融治疗

  • 以往局部消融常用于早期肝脏肿瘤的治疗,而近期有学者发现局部消融可以与TACE等治疗方式联用,将初始判断无手术指征的肝细胞肝癌患者进行转化治疗,尤其对肿瘤大于5 cm的患者[31]。但局部消融在ICC中的研究较少,有两项研究指出局部消融治疗仅可用于较小(<2 cm) 且没有血管侵犯的ICC,反之治疗效果会显著下降[32, 33],这也严重限制了局部消融治疗在ICC转化治疗中的应用。

  • 2.5 靶向治疗

  • ICC相较于正常胆管内皮细胞存在着诸多基因突变,最近的一些研究逐渐确认了若干ICC致癌的关键驱动基因,并以之为靶点,研制了各类靶向药物。这些靶向药物针对的靶点各异,效果也各异。 目前尚无相关研究探讨靶向药物用于转化治疗的效果,但靶向药物治疗进展期ICC的相关研究结果也可以为其用于转化治疗提供一定的理论依据。

  • 2.5.1 成纤维细胞生长因子受体(Fibroblast Growth Factor Receptor,FGFR) 变异

  • FGFR是一类酪氨酸激酶受体,与成纤维细胞生长因子结合并激活后,FGFR可促进自身发生磷酸化,并激活下游丝裂原活化蛋白激酶(Mitogenactivated Protein Kinase, MAPK) 和蛋白激酶B(Protein Kinase B,PKB/AKT) 通路,进而参与细胞的生理功能。多种肿瘤中均存在FGFR的变异, 而11%~45%的ICC中主要存在的是FGFR2 变异, FGFR2的变异会导致下游酪氨酸激酶的持续激活, 从而促进肿瘤的增殖和侵袭[34, 35]。目前针对ICC已有多种FGFR抑制剂在实际临床或临床试验中取得了较理想的效果。

  • 2.5.1.1 英菲格拉替尼Infigratinib/BGJ398

  • BGJ398 是最早研发的选择性FGFR抑制剂之一。2018 年的一项Ⅱ期临床试验测试了BGJ398 在还有FGFR突变的进展期ICC患者中的效果,该临床试验包含有48名FGFR2融合患者,8名FGFR2 突变患者,3名FGFR2扩增患者[36]。结果显示BGJ398在这些病人中的总体缓解率为14.8%,疾病控制率为75.4%,平均无进展生存期为5.8 个月,而且BGJ398 对FGFR融合变异的患者效果更加显著, 总体缓解率可达到18.8%,疾病控制率更达到了83.3%。其他一些临床研究也正在进行中,例如临床试验NCT03773302正在使用BGJ398 作为一线治疗方案治疗具有FGFR2 融合或移位的胆管癌患者,NCT02150967 尝试使用BGJ398 治疗铂类药物治疗失败的具有FGFR变异的进展期胆管癌患者, NCT04233567 则考虑进行临床试验验证BGJ398 在多种实体肿瘤中的疗效,包括ICC。

  • 2.5.1.2 Derazantinib

  • Derazantinib是一种多效FGFR抑制剂,在体外细胞和动物实验中可以显著抑制肿瘤细胞的增殖。 在一项Ⅱ期临床试验中,29 名无法耐受一线系统化疗或化疗失败且含有FGFR融合变异的进展期ICC患者接受了Derazantinib的治疗[37]。结果显示, 经过Derazantinib的治疗,肿瘤的总体缓解率为20.7%,疾病控制率可高达82.8%,估计平均无进展生存期为5.7 个月,且不良反应较轻微。另外临床试验NCT01752920 已于2019 年完成患者纳入, 正在进行后期的随访和数据分析,该临床试验研究了Derazantinib在多种含有FGFR变异的实体肿瘤患者中的效果。此外,2017 年梅奥诊所牵头启动了一项临床试验NCT03230318,旨在探究Derazantinib治疗含有FGFR变异的进展期或不可切除的ICC的效果。

  • 2.5.1.3 Pemigatinib

  • 2020 年4 月17 日Pemigatinib被美国食品药品监督管理局(Food and Drug Administration,FDA) 批准用于治疗既往接受过治疗的FGFR2 融合或重排的局部晚期或转移性胆管癌患者,这是FDA批准的首个胆管癌靶向药物。在此之前,Pemigatinib治疗FGFR2 融合或重排的局部晚期或转移性胆管癌患者已经被验证。Abou-Alfa等的多中心Ⅱ期临床试验纳入了146名FGFR2变异的胆管癌患者,包括107名FGFR融合或重排患者,20名其他FGFR变异患者,18名无FGFR变异患者,1名不确定FGFR变异患者[38]。最终有3名患者病情获得了完全缓解(Complete Response,CR),35 名患者病情获得了PR,没有患者因为治疗相关因素死亡,但有65名患者(45%) 出现了严重的不良反应,如腹痛、发热、 胆管炎等。临床试验NCT03656536目前也正在进行中,其旨在比较Pemigatinib与传统系统化疗用于治疗不可切除的胆管癌的疗效, 而临床试验NCT04088188 则尝试联用Pemigatinib与吉西他滨加顺铂的化疗方案治疗进展期胆管癌。

  • 2.5.1.4 Futibatinib/TAS-120

  • 多数FGFR抑制剂为ATP竞争型抑制剂,此类FGFR抑制剂很可能会因为肿瘤出现其他FGFR变异位点而失去治疗效果。TAS-120则是一种不可逆结合型FGFR抑制剂,Goyal等的研究使用4 名对BGJ398 耐药的ICC患者的肿瘤标本构建了体外模型,发现TAS-120对于这类对ATP竞争型FGFR抑制剂耐药的肿瘤仍然具有很强的抑制作用[39]。而相关的临床试验也正在准备中, 临床试验NCT04507503 准备将TAS-120 用于含有FGFR2 重排的进展期胆管癌患者的治疗,NCT04093362 则计划将TAS-120与一线化疗方案吉西他滨联合顺铂的疗效进行比较。

  • 2.5.2 异柠檬酸脱氢酶(Isocitrate Dehydrogenase, IDH) 1/2变异

  • IDH是细胞能量代谢的关键限速酶之一,而IDH基因的变异常会出现在ICC中,约占总ICC的14%[40]。IDH的变异会明显增加肿瘤的增殖能力, 而针对这一基因位点的变异,有多种抑制剂被开发,其中最常用的为艾伏尼布(Ivosidenib/AG120)。2019年AG-120的疗效和安全性在一项多中心I期临床试验中被验证,在这项试验中73名存在IDH1 变异的ICC患者为研究对象,在接受了AG120 的治疗后,有4 名患者(5%) 病情获得了PR, 平均无进展生存期为3.8个月、6个月和12个月、无进展生存率分别为40.1%和21.8%,而平均总体生存时间为13.8个月[41]。这项试验没有限制使用药物剂量,因此部分患者在服用了大剂量药物后出现了明显的不良反应,甚至有2名患者因不良反应而死亡。而在另外一项大型Ⅲ期多中心随机双盲临床试验中,185 名存在IDH变异且系统化疗无效的ICC患者参与了试验,其中124 名患者接受了AG-120 治疗,61名患者接受了安慰剂治疗,结果显示,AG120组患者平均无进展生存时间较安慰剂组明显延长(2.7个月比1.4个月),且无患者因不良反应而死亡[42]。除此之外,目前还有一些其他的临床试验在研究AG-120 治疗ICC的疗效,如NCT02989857 和NCT02073994,但总体来说AG-120 并没有体现出类似于FGFR抑制剂的疗效。

  • 其他IDH抑制剂如Enasidenib也在进行相关的临床试验,如NCT02273739,实际的应用价值还有待试验结果的验证。

  • 2.5.3 表皮生长因子受体家族(Epidermal Growth Factor Receptor Family,HER) 变异

  • 相较于肝门胆管癌和肝外胆管癌,ICC出现HER变异的几率较小,仅约4.8%[43],正因为如此, 针对HER的药物治疗效果并不理想。目前有两种类型的抗HER药物,一种是单克隆抗体,另一种是配体阻滞剂。近期的一项meta分析结果显示, 当HER单克隆抗体与吉西他滨联合顺铂的化疗方案联用时,效果并没有优于单独使用吉西他滨联合顺铂的化疗方案,且会明显增加不良反应的发生率[44]。在配体阻滞剂方面,一项临床试验探讨了卡博替尼(cabozantinib) 治疗进展期胆管癌患者的疗效,该试验纳入了19 名患者,其中16 名为ICC患者,在使用了卡博替尼治疗后,患者的平均总体生存时间为5.2个月,平均无进展生存时间仅为1.8 个月,且不良反应显著[45]。因此,抗HER类药物目前并不能优先考虑用于ICC的治疗。

  • 2.5.4 其他基因变异

  • 在基础研究中,针对ICC的基因分析发现了诸多特异性基因变异,如丝裂原活化蛋白激酶(MitogenActivated Protein Kinases,MAPK)通路,酪氨酸激酶A(Tyrosine Kinase A,TrkA),乳腺癌易感基因(Breast Cancer Susceptibility Genes,BRCA)等,根据这些基因变异研发的药物目前正在进行相应的动物和临床试验,其治疗效果与不良反应还有待探讨。

  • 2.6 联合免疫治疗

  • 肿瘤独特的免疫微环境使得肿瘤可以逃避人体免疫系统的攻击,目前的研究表明肿瘤细胞可以分泌多种物质激活免疫细胞表面的免疫检查点分子, 如程序性死亡受体1(Programmed Death-1,PD-1)、 细胞毒性T淋巴细胞相关蛋白4(Cytotoxic T Lymphocyte Antigen 4,CTLA4)、T细胞免疫球蛋白黏蛋白3(T Cell Immunoglobulin-3,Tim-3)和淋巴细胞激活基因3(Lymphocyte Activation Gene-3, LAG-3) 等,从而抑制免疫细胞的活性,进而逃避攻击。针对这一特点,多种免疫检查点抑制剂被研发出来用以治疗恶性肿瘤,也包括ICC。

  • 2.6.1 派姆单抗(Pembrolizumab)

  • 派姆单抗是一种抗PD-1 抗体,其已被证实在治疗肺癌时可获得显著疗效,且已被美国FDA批准用于实体肿瘤的治疗,但其在ICC的治疗中效果尚不十分明确。在一项多中心回顾性研究中,51 名PD-1 阳性的难治性胆管癌患者接受了派姆单抗的治疗,结果5名患者(9.8%) 病情可以获得PR, 平均无进展生存时间为2.1 个月,平均总生存时间为6.9 个月,且只有少数患者出现较为严重的不良反应[46]。另一项回顾性研究也分析了40 名接受派姆单抗治疗的难治性胆管癌患者的预后情况,结果显示4名患者(10%) 病情获得了PR,且有1名患者病情获得了完全缓解[47]。派姆单抗在胆管癌中的治疗效果已成为一大热点,目前已知的有关派姆单抗治疗胆管癌的临床试验已多达十余项,这些临床试验的结果可以为派姆单抗的临床使用提供更为可靠的循证医学证据。

  • 2.6.2 纳武单抗(Nivolumab)

  • 纳武单抗是一种人免疫球蛋白G4(IgG4) 单克隆抗体,其主要是与PD-1 的受体结合以抑制其活性。近期的一些临床研究多肯定了纳武单抗在治疗胆管癌时的疗效。解放军总医院的一项前瞻性临床研究显示,30 名转移性胆管癌患者接受了纳武单抗的治疗,其中1名患者病情获得了CR,5名患者获得了PR,12名患者被评价为SD,12名患者被评价为PD,平均无进展生存时间为3.1个月,并且在联用系统化疗时可以取得更好的疗效[48]。日本的一项多中心非随机研究显示,对于无法切除或复发的胆管癌患者,若患者无法耐受系统化疗或系统化疗无效,接受纳武单抗治疗后平均总体生存时间为5.2 个月;若患者同时接受系统化疗和纳武单抗治疗,患者平均总体生存时间可达到15.4个月[49]。另一项Ⅱ期多中心临床试验也确认了纳武单抗的疗效,该试验纳入了54名难治性进展期胆管癌患者, 均接受纳武单抗治疗,最终10 名患者病情获得了PR,平均无进展生存时间为3.68 个月,平均总体生存时间达到了14.24 个月[50]。这些研究结果也显示,纳武单抗治疗胆管癌是比较安全的,不良反应的发生较少,且症状较轻微,这也进一步提升了纳武单抗的应用价值。

  • 2.6.3 替雷利珠单抗(Tislelizumab)

  • 替雷利珠单抗是我国近期研发的PD-1 免疫检查点抑制剂,其与纳武单抗类似,也是一种IgG4 单克隆抗体,最近的两项Ⅰ/Ⅱ期临床试验都验证了替雷利珠单抗用于治疗实体肿瘤的疗效,其中也包括ICC[51, 52]

  • 2.6.4 依匹莫单抗(Ipilumumab)

  • 依匹莫单抗是最经典的抗CTLA-4抗体,其被证明可用于治疗多种恶性肿瘤,包括肝细胞肝癌、 黑色素瘤和肾癌等[53-55],但在ICC患者中依匹莫单抗的疗效没有得到证实。一项Ⅱ期非随机临床试验显示联用纳武单抗和依匹莫单抗治疗的进展期胆管癌患者,PR率可达23%,平均总体生存时间为5.7 个月,有15%的患者出现了较严重的不良反应[56]。 该研究提示多药联用可能无法进一步提高单药的效果,并且不良反应的发生率也会明显升高,而依匹莫单抗单药的效果还需要研究进一步证实。

  • 3 实践经验

  • 笔者单位在2013年1月至2020年7月间收治的249 名ICC患者中,初始不存在手术指征的患者有71 名,其中有29 名患者发现时已有远处转移,只能给予姑息保守治疗。剩余42 名患者接受了不同的辅助治疗,以期对其进行降期转化,包括20 名接受系统化疗患者,5 名接受靶向治疗患者,6 名接受TACE治疗患者,4名接受射频消融患者,3名接受放射治疗患者,1 名接受免疫治疗患者,3 名接受联合治疗患者。最终共有9名患者(21%) 在接受转化治疗后符合了手术指征,进行了根治性手术,其中5名患者接受了系统化疗,1名患者接受靶向治疗,1名患者接受TACE治疗,1名患者接受放射治疗,1名患者接受系统化疗联合靶向治疗。这9名患者中随访时间超过1年的共有4名,一年总体生存率100%。本团队于2017 年国内首次报告了ICC转化治疗一例[57],下面笔者结合该病例以及近期一例转化成功病例介绍转化治疗的具体实施过程。

  • 第一例ICC患者,69岁男性,T2N1M0期,因考虑肿瘤存在淋巴结转移和血管侵犯,无法手术切除,故先行吉西他滨1 000 mg/m2 +奥沙利铂130 mg/m2 第1 天,吉西他滨1 000 mg/m2 第8 天(GEMOX方案) 化疗。4 个周期化疗后肿瘤及淋巴结明显缩小(见图1),于2016年8月6日行肝中叶切除术+左肝结节活检+胆囊切除+第7、8、9、12、 13 组淋巴结清扫术,手术切缘及淋巴结均阴性。 术后继续给予病人2 个周期GEMOX化疗。随访中,患者于2018 年12 月发现肺转移,2019 年8 月发现广泛腹腔转移。患者术后无复发生存时间26 个月,总生存时间为39个月。

  • 第二例病例患者男性,62 岁, 2020 年4 月11 日因“右上腹胀痛一月余”来我院就诊,其余无特殊症状,全腹部增强CT扫描提示左肝肿块累及肝 Ⅷ段及Ⅰ段,并侵犯肝中和肝左静脉、门脉左支, 肝门部及后腹膜多发轻度肿大淋巴结。2020年4月15 日行超声引导下肝肿块穿刺活检,病理结果提示低分化癌,首先考虑胆管细胞癌,合并血管侵犯,分期为T2N1M0期,为局部进展期病人。考虑于2020 年4 月18 日开始行吉西他滨1.6 g联合白蛋白紫杉醇200 mg(AG方案) 静脉化疗,化疗过程顺利,患者无明显不适主诉。患者经过6 次AG方案化疗联合1 次SBRT后,影像检查提示肿瘤从初始的8.6×6.5 cm缩小至3.1×2.2 cm,疗效评定为PR(见图2)。于2020 年8 月24 日接受了左半肝切除术+肝Ⅷ段部分切除术+胆囊切除术+第1、3、7、 8、12 组淋巴结清扫+第一二三肝门解剖术,常规病理结果提示:左肝中-低分化胆管细胞癌,大小2.5×2 cm,手术切缘阴性,第1、3、7、8、12组淋巴结均阴性。肝中静脉近心端和远心端切缘均为阴性。患者术后恢复良好,目前计划术后完成2周期的AG化疗方案。

  • 图1 患者入院时(A) 和接受4个周期化疗后(B) 的腹部磁共振图像

  • 图2 患者入院时(A) 和接受6次化疗后(B) 的腹部磁共振图像

  • ICC转化治疗的成功与否关键在于肿瘤对转化治疗方式的敏感性,上述病例患者肿瘤对AG化疗方案非常敏感,根据磁共振结果6次化疗后肿瘤直径缩小了一半以上,血管侵犯情况也得到了明显改善,因此从不可手术转化为根治性手术。但目前来看转化治疗的总体成功率还处于比较低的状态,笔者单位转化成功率仅为21%。国外报告转化成功率13.9%~20.8%,基于吉西他滨的系统化疗作为ICC一线治疗方案,在进行转化治疗时使用最多,但在总体的转化率上与其他治疗方式没有显著的差异。

  • 4 展望

  • 总体来说,目前进展期ICC的转化治疗中主要存在以下问题:(1) 转化治疗的方法首选系统性化疗方案,但选择化疗药物时仍以既往经验为根据, 因此系统性化疗的治疗效果并不理想。尽管精准治疗和基因检测可提供部分药物选择依据,但有意义的基因检测发生率很低,还有待发现更明确的靶点;(2) 转化治疗有效后是否需结合介入、放疗等局部治疗并无标准模式,化疗结束后等待手术的间歇期需多长也没有判断标准,有待进一步总结和展开;(3) 关于ICC的分型,目前只有临床病理分型,有待建立通用的临床分型。本团队目前主要将ICC分成段型、支型和叶型等三种临床分型[58],这种分型有利于临床诊断和治疗决策。

  • 综上所述,随着经验的积累,ICC转化治疗的效果逐渐得到验证,为该类病人的长期生存带来了曙光。与此同时,作为一种新的治疗理念和模式, 其目前尚存在一些问题,还需要研究者不断总结, 对适应症、转化方法、根治性切除的标准等问题进行研究,以使其成为一种能有效改善ICC长期生存的治疗模式。

  • 参考文献

    • [1] BANALES J M,CARDINALE V,CARPINO G,et al.Cholangiocarcinoma:current knowledge and future perspectives consensus statement from the european network for the study of cholangiocarcinoma(ENS-CCA)[J].Nat Rev Gastroenterol Hepatol,2016,13(5):261-80.

    • [2] 吴锦洪,李江涛.肝内胆管细胞癌的淋巴结清扫:共识和争议[J].肝胆外科杂志,2016,24(5):321-323.

    • [3] BERTUCCIO P,MALVEZZI M,CARIOLI G,et al.Global trends in mortality from intrahepatic and extrahepatic cholangiocarcinoma[J].J Hepatol,2019,71(1):104-114.

    • [4] ZHOU Z,NIE S D,JIANG B,et al.Risk factors for extrahepatic cholangiocarcinoma:a case-control study in China[J].European Journal of Cancer Prevention,2019,28(4):254-257.

    • [5] VAN VUGT J L A,GASPERSZ M P,COELEN R J S,et al.The prognostic value of portal vein and hepatic artery involvement in patients with perihilar cholangiocarcinoma[J].HPB(Oxford),2018,20(1):83-92.

    • [6] GROOT KOERKAMP B,WIGGERS J K,ALLEN P J,et al.Recurrence rate and pattern of perihilar cholangiocarcinoma after curative intent resection[J].J Am Coll Surg,2015,221(6):1041-1049.

    • [7] SPOLVERATO G,KIM Y,ALEXANDRESCU S,et al.Management and outcomes of patients with recurrent intrahepatic cholangiocarcinoma following previous curativeintent surgical resection[J].Ann Surg Oncol,2016,23(1):235-243.

    • [8] SIRICA A E,GORES G J,GROOPMAN J D,et al.Intrahepatic cholangiocarcinoma:continuing challenges and translational advances[J].Hepatology,2019,69(4):1803-1815.

    • [9] BISMUTH H,ADAM R,LEVI F,et al.Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy[J].Ann Surg,1996,224(4):509-520,discussion 20-22.

    • [10] 江杰,胡宗强,陈刚,等.原发性肝癌转化治疗研究进展[J].临床肝胆病杂志,2020,36(8):1870-1873.

    • [11] 何霞飞,周永宁,关泉林.Ⅳ期胃癌转化治疗现状[J].肿瘤药学,2020,10(2):139-147,165.

    • [12] WANG T,WANG N,REN H,et al.Long-term results of conversion therapy for initially unresectable gastric cancer:analysis of 122 patients at the National Cancer Center in China[J].Journal of Cancer,2019,10(24):5975-5985.

    • [13] RIBY D,MAZZOTTA A D,BERGEAT D,et al.Downstaging with radioembolization or chemotherapy for initially unresectable intrahepatic cholangiocarcinoma[J].Ann Surg Oncol,2020,27:3729-3737.

    • [14] LE ROY B,GELLI M,PITTAU G,et al.Neoadjuvant chemotherapy for initially unresectable intrahepatic cholangiocarcinoma[J].Br J Surg,2018,105(7):839-47.

    • [15] CHO Y,KIM T H,SEONG J.Improved oncologic out-come with chemoradiotherapy followed by surgery in unresectable intrahepatic cholangiocarcinoma[J].Strahlentherapie und Onkologie,2017,193(8):620-629.

    • [16] ULUSAKARYA A,KARABOUE A,CIACIO O,et al.A retrospective study of patient-tailored FOLFIRINOX as a first-line chemotherapy for patients with advanced biliary tract cancer[J].BMC Cancer,2020,20(1):515.

    • [17] SHROFF R T,JAVLE M M,XIAO L,et al.Gemcitabine,cisplatin,and nab-paclitaxel for the treatment of advanced biliary tract cancers:a phase 2 clinical trial[J].JAMA Oncol,2019,5(6):824-830.

    • [18] SHAO F,QI W,MENG F T,et al.Role of palliative radiotherapy in unresectable intrahepatic cholangiocarcinoma:population-based analysis with propensity score matching[J].Cancer Management and Research,2018,10:1497-1506.

    • [19] SUMIYOSHI T,SHIMA Y,OKABAYASHI T,et al.Chemoradiotherapy for initially unresectable locally advanced cholangiocarcinoma[J].World J Surg,2018,42(9):2910-2918.

    • [20] VERMA V,KUSI APPIAH A,LAUTENSCHLAEGER T,et al.Chemoradiotherapy versus chemotherapy alone for unresected intrahepatic cholangiocarcinoma:practice patterns and outcomes from the national cancer data base[J].Journal of Gastrointestinal Oncology,2018,9(3):527-535.

    • [21] BURGER I,HONG K,SCHULICK R,et al.Transcatheter arterial chemoembolization in unresectable cholangiocarcinoma:initial experience in a single institution[J].J Vasc Interv Radiol,2005,16(3):353-561.

    • [22] PARK S Y,KIM J H,YOON H J,et al.Transarterial chemoembolization versus supportive therapy in the palliative treatment of unresectable intrahepatic cholangiocarcinoma[J].Clin Radiol,2011,66(4):322-328.

    • [23] KIM J H,YOON H K,SUNG K B,et al.Transcatheter arterial chemoembolization or chemoinfusion for unresectable intrahepatic cholangiocarcinoma:clinical efficacy and factors influencing outcomes[J].Cancer,2008,113(7):1614-1622.

    • [24] HERBER S,OTTO G,SCHNEIDER J,et al.Transarterial chemoembolization(TACE)for inoperable intrahepatic cholangiocarcinoma[J].Cardiovasc Intervent Radiol,2007,30(6):1156-1165.

    • [25] VOGL T J,NAGUIB N N,NOUR-ELDIN N E,et al.Transarterial chemoembolization in the treatment of patients with unresectable cholangiocarcinoma:results and prognostic factors governing treatment success[J].Int J Cancer,2012,131(3):733-740.

    • [26] ZHOU T Y,ZHOU G H,ZHANG Y L,et al.Drug-eluting beads transarterial chemoembolization with CalliSpheres microspheres for treatment of unresectable intrahepatic cholangiocarcinoma[J].Journal of Cancer,2020,11(15):4534-4541.

    • [27] KUHLMANN J B,EURINGER W,SPANGENBERG H C,et al.Treatment of unresectable cholangiocarcinoma:conventional transarterial chemoembolization compared with drug eluting bead-transarterial chemoembolization and systemic chemotherapy[J].Eur J Gastroenterol Hepatol,2012,24(4):437-443.

    • [28] AL-ADRA D P,GILL R S,AXFORD S J,et al.Treatment of unresectable intrahepatic cholangiocarcinoma with yttrium-90 radioembolization:a systematic review and pooled analysis[J].Eur J Surg Oncol,2015,41(1):120-127.

    • [29] AKINWANDE O,SHAH V,MILLS A,et al.Chemoembolization versus radioembolization for the treatment of unresectable intrahepatic cholangiocarcinoma in a single institution image-based efficacy and comparative toxic-ity[J].Hepatic Oncology,2017,4(3):75-81.

    • [30] BUETTNER S,BRAAT A,MARGONIS GA,et al.Yttrium-90 radioembolization in intrahepatic cholangiocarcinoma:a multicenter retrospective analysis[J].J Vasc Interv Radiol,2020,31(7):1035-1043.

    • [31] WANG L,KE Q,LIN N,et al.The efficacy of transarterial chemoembolization combined with microwave ablation for unresectable hepatocellular carcinoma:a systematic review and meta-analysis[J].International Journal of Hyperthermia,2019,36(1):1288-1296.

    • [32] WU L,TSILIMIGRAS D I,FAROOQ A,et al.Potential survival benefit of radiofrequency ablation for small solitary intrahepatic cholangiocarcinoma in nonsurgically managed patients:a population-based analysis[J].J Surg Oncol,2019,120(8):1358-1364.

    • [33] BRANDI G,RIZZO A,DALL'OLIO F G,et al.Percutaneous radiofrequency ablation in intrahepatic cholangiocarcinoma:a retrospective single-center experience[J].International Journal of Hyperthermia,2020,37(1):479-485.

    • [34] MASSIRONI S,PILLA L,ELVEVI A,et al.New and emerging systemic therapeutic options for advanced cholangiocarcinoma[J].Cells,2020,9(3):688.

    • [35] LOUIS C,PAPOUTSOGLOU P,COULOUARN C.Molecular classification of cholangiocarcinoma[J].Curr Opin Gastroenterol,2020,36(2):57-62.

    • [36] JAVLE M,LOWERY M,SHROFF R T,et al.Phase Ⅱstudy of BGJ398 in patients with FGFR-altered advancedcholangiocarcinoma[J].J Clin Oncol,2018,36(3):276-282.

    • [37] MAZZAFERRO V,EL-RAYES B F,DROZ DIT BUSSET M,et al.Derazantinib(ARQ 087)in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma[J].Br J Cancer,2019,120(2):165-171.

    • [38] ABOU-ALFA G K,SAHAI V,HOLLEBECQUE A,et al.Pemigatinib for previously treated,locally advanced or metastatic cholangiocarcinoma:a multicentre,open-label,phase 2 study[J].Lancet Oncol,2020,21(5):671-684.

    • [39] GOYAL L,SHI L,LIU L Y,et al.TAS-120 overcomes resistance to ATP-competitive FGFR inhibitors in patients with FGFR2 fusion-positive intrahepatic cholangiocarcinoma[J].Cancer Discovery,2019,9(8):1064-1079.

    • [40] BORGER D R,TANABE K K,FAN K C,et al.Frequent mutation of isocitrate dehydrogenase(IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping[J].Oncologist,2012,17(1):72-79.

    • [41] LOWERY M A,BURRIS H A,JANKU F,et al.Safety and activity of ivosidenib in patients with IDH1-mutant advanced cholangiocarcinoma:a phase 1 study[J].The Lancet Gastroenterology & Hepatology,2019,4(9):711-720.

    • [42] ABOU-ALFA G K,MACARULLA T,JAVLE M M,et al.Ivosidenib in IDH1-mutant,chemotherapy-refractory cholangiocarcinoma(ClarIDHy):a multicentre,randomised,double-blind,placebo-controlled,phase 3 study[J].Lancet Oncol,2020,21(6):796-807.

    • [43] GALDY S,LAMARCA A,MCNAMARA M G,et al.HER2/HER3 pathway in biliary tract malignancies;systematic review and meta-analysis:a potential therapeutic target?[J].Cancer Metastasis Reviews,2017,36(1):141-157.

    • [44] RIZZO A,FREGA G,RICCI A D,et al.Anti-EGFR monoclonal antibodies in advanced biliary tract cancer:a systematic review and meta-analysis[J].In Vivo,2020,34(2):479-488.

    • [45] GOYAL L,ZHENG H,YURGELUN M B,et al.A phase 2 and biomarker study of cabozantinib in patients with advanced cholangiocarcinoma[J].Cancer,2017,123(11):1979-1988.

    • [46] LEE S H,LEE H S,LEE S H,et al.Efficacy and safety of pembrolizumab for gemcitabine/cisplatin-refractory biliary tract cancer:a multicenter retrospective study[J].Journal of Clinical Medicine,2020,9(6):1769.

    • [47] KANG J,JEONG J H,HWANG H S,et al.Efficacy and safety of pembrolizumab in patients with refractory advanced biliary tract cancer:tumor proportion score as a potential biomarker for response[J].Cancer Research and Treatment,2020,52(2):594-603.

    • [48] GOU M,ZHANG Y,SI H,et al.Efficacy and safety of nivolumab for metastatic biliary tract cancer[J].OncoTargets and Therapy,2019,12:861-867.

    • [49] UENO M,IKEDA M,MORIZANE C,et al.Nivolumab alone or in combination with cisplatin plus gemcitabine in Japanese patients with unresectable or recurrent biliary tract cancer:a non-randomised,multicentre,open-label,phase 1 study[J].The Lancet Gastroenterology & Hepatology,2019,4(8):611-621.

    • [50] KIM R D,CHUNG V,ALESE O B,et al.A Phase 2 multi-institutional study of nivolumab for patients with advanced refractory biliary tract cancer [J].JAMA Oncol,2020,6(6):888-894.

    • [51] SHEN L,GUO J,ZHANG Q,et al.Tislelizumab in Chinese patients with advanced solid tumors:an open-label,non-comparative,phase 1/2 study[J].Journal for Immunotherapy of Cancer,2020,8(1):e000437.

    • [52] DESAI J,DEVA S,LEE J S,et al.Phase IA/IB study of single-agent tislelizumab,an investigational anti-PD-1 antibody,in solid tumors[J].Journal for Immunotherapy of Cancer,2020,8(1):e000453.

    • [53] MOSER J C,PULIDO J S,DRONCA R S,et al.The Mayo Clinic experience with the use of kinase inhibitors,ipilimumab,bevacizumab,and local therapies in the treatment of metastatic uveal melanoma[J].Melanoma Research,2015,25(1):59-63.

    • [54] LIANG T Z,WHANG G,CHOPRA S.Primary hepatic carcinoma with inhibin positivity in a young male patient:a rare tumor previously only reported in females-case report and review of literature[J].Virchows Archiv,2020.

    • [55] INOZUME T,HANADA K,WANG Q J,et al.IL-17 secreted by tumor reactive T cells induces IL-8 release by human renal cancer cells[J].Journal of Immunotherapy,2009,32(2):109-117.

    • [56] KLEIN O,KEE D,NAGRIAL A,et al.Evaluation of combination nivolumab and ipilimumab immunotherapy in patients with advanced biliary tract cancers:subgroup analysis of a phase 2 nonrandomized clinical trial[J].JAMA Oncol,2020,6(9):1405-1409.

    • [57] 吴锦洪,周冬儿,于源泉,等.肝内胆管癌新辅助化疗后手术切除1例报告并文献复习[J].中国实用外科杂志,2017,37(7):818-820,822.

    • [58] 彭淑牖,王许安,黄从云,等.以实际解剖部位命名的分型法:对五种胆道疾病分型的思考[J].中华外科杂志,2019,57(6):412-417.

  • 参考文献

    • [1] BANALES J M,CARDINALE V,CARPINO G,et al.Cholangiocarcinoma:current knowledge and future perspectives consensus statement from the european network for the study of cholangiocarcinoma(ENS-CCA)[J].Nat Rev Gastroenterol Hepatol,2016,13(5):261-80.

    • [2] 吴锦洪,李江涛.肝内胆管细胞癌的淋巴结清扫:共识和争议[J].肝胆外科杂志,2016,24(5):321-323.

    • [3] BERTUCCIO P,MALVEZZI M,CARIOLI G,et al.Global trends in mortality from intrahepatic and extrahepatic cholangiocarcinoma[J].J Hepatol,2019,71(1):104-114.

    • [4] ZHOU Z,NIE S D,JIANG B,et al.Risk factors for extrahepatic cholangiocarcinoma:a case-control study in China[J].European Journal of Cancer Prevention,2019,28(4):254-257.

    • [5] VAN VUGT J L A,GASPERSZ M P,COELEN R J S,et al.The prognostic value of portal vein and hepatic artery involvement in patients with perihilar cholangiocarcinoma[J].HPB(Oxford),2018,20(1):83-92.

    • [6] GROOT KOERKAMP B,WIGGERS J K,ALLEN P J,et al.Recurrence rate and pattern of perihilar cholangiocarcinoma after curative intent resection[J].J Am Coll Surg,2015,221(6):1041-1049.

    • [7] SPOLVERATO G,KIM Y,ALEXANDRESCU S,et al.Management and outcomes of patients with recurrent intrahepatic cholangiocarcinoma following previous curativeintent surgical resection[J].Ann Surg Oncol,2016,23(1):235-243.

    • [8] SIRICA A E,GORES G J,GROOPMAN J D,et al.Intrahepatic cholangiocarcinoma:continuing challenges and translational advances[J].Hepatology,2019,69(4):1803-1815.

    • [9] BISMUTH H,ADAM R,LEVI F,et al.Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy[J].Ann Surg,1996,224(4):509-520,discussion 20-22.

    • [10] 江杰,胡宗强,陈刚,等.原发性肝癌转化治疗研究进展[J].临床肝胆病杂志,2020,36(8):1870-1873.

    • [11] 何霞飞,周永宁,关泉林.Ⅳ期胃癌转化治疗现状[J].肿瘤药学,2020,10(2):139-147,165.

    • [12] WANG T,WANG N,REN H,et al.Long-term results of conversion therapy for initially unresectable gastric cancer:analysis of 122 patients at the National Cancer Center in China[J].Journal of Cancer,2019,10(24):5975-5985.

    • [13] RIBY D,MAZZOTTA A D,BERGEAT D,et al.Downstaging with radioembolization or chemotherapy for initially unresectable intrahepatic cholangiocarcinoma[J].Ann Surg Oncol,2020,27:3729-3737.

    • [14] LE ROY B,GELLI M,PITTAU G,et al.Neoadjuvant chemotherapy for initially unresectable intrahepatic cholangiocarcinoma[J].Br J Surg,2018,105(7):839-47.

    • [15] CHO Y,KIM T H,SEONG J.Improved oncologic out-come with chemoradiotherapy followed by surgery in unresectable intrahepatic cholangiocarcinoma[J].Strahlentherapie und Onkologie,2017,193(8):620-629.

    • [16] ULUSAKARYA A,KARABOUE A,CIACIO O,et al.A retrospective study of patient-tailored FOLFIRINOX as a first-line chemotherapy for patients with advanced biliary tract cancer[J].BMC Cancer,2020,20(1):515.

    • [17] SHROFF R T,JAVLE M M,XIAO L,et al.Gemcitabine,cisplatin,and nab-paclitaxel for the treatment of advanced biliary tract cancers:a phase 2 clinical trial[J].JAMA Oncol,2019,5(6):824-830.

    • [18] SHAO F,QI W,MENG F T,et al.Role of palliative radiotherapy in unresectable intrahepatic cholangiocarcinoma:population-based analysis with propensity score matching[J].Cancer Management and Research,2018,10:1497-1506.

    • [19] SUMIYOSHI T,SHIMA Y,OKABAYASHI T,et al.Chemoradiotherapy for initially unresectable locally advanced cholangiocarcinoma[J].World J Surg,2018,42(9):2910-2918.

    • [20] VERMA V,KUSI APPIAH A,LAUTENSCHLAEGER T,et al.Chemoradiotherapy versus chemotherapy alone for unresected intrahepatic cholangiocarcinoma:practice patterns and outcomes from the national cancer data base[J].Journal of Gastrointestinal Oncology,2018,9(3):527-535.

    • [21] BURGER I,HONG K,SCHULICK R,et al.Transcatheter arterial chemoembolization in unresectable cholangiocarcinoma:initial experience in a single institution[J].J Vasc Interv Radiol,2005,16(3):353-561.

    • [22] PARK S Y,KIM J H,YOON H J,et al.Transarterial chemoembolization versus supportive therapy in the palliative treatment of unresectable intrahepatic cholangiocarcinoma[J].Clin Radiol,2011,66(4):322-328.

    • [23] KIM J H,YOON H K,SUNG K B,et al.Transcatheter arterial chemoembolization or chemoinfusion for unresectable intrahepatic cholangiocarcinoma:clinical efficacy and factors influencing outcomes[J].Cancer,2008,113(7):1614-1622.

    • [24] HERBER S,OTTO G,SCHNEIDER J,et al.Transarterial chemoembolization(TACE)for inoperable intrahepatic cholangiocarcinoma[J].Cardiovasc Intervent Radiol,2007,30(6):1156-1165.

    • [25] VOGL T J,NAGUIB N N,NOUR-ELDIN N E,et al.Transarterial chemoembolization in the treatment of patients with unresectable cholangiocarcinoma:results and prognostic factors governing treatment success[J].Int J Cancer,2012,131(3):733-740.

    • [26] ZHOU T Y,ZHOU G H,ZHANG Y L,et al.Drug-eluting beads transarterial chemoembolization with CalliSpheres microspheres for treatment of unresectable intrahepatic cholangiocarcinoma[J].Journal of Cancer,2020,11(15):4534-4541.

    • [27] KUHLMANN J B,EURINGER W,SPANGENBERG H C,et al.Treatment of unresectable cholangiocarcinoma:conventional transarterial chemoembolization compared with drug eluting bead-transarterial chemoembolization and systemic chemotherapy[J].Eur J Gastroenterol Hepatol,2012,24(4):437-443.

    • [28] AL-ADRA D P,GILL R S,AXFORD S J,et al.Treatment of unresectable intrahepatic cholangiocarcinoma with yttrium-90 radioembolization:a systematic review and pooled analysis[J].Eur J Surg Oncol,2015,41(1):120-127.

    • [29] AKINWANDE O,SHAH V,MILLS A,et al.Chemoembolization versus radioembolization for the treatment of unresectable intrahepatic cholangiocarcinoma in a single institution image-based efficacy and comparative toxic-ity[J].Hepatic Oncology,2017,4(3):75-81.

    • [30] BUETTNER S,BRAAT A,MARGONIS GA,et al.Yttrium-90 radioembolization in intrahepatic cholangiocarcinoma:a multicenter retrospective analysis[J].J Vasc Interv Radiol,2020,31(7):1035-1043.

    • [31] WANG L,KE Q,LIN N,et al.The efficacy of transarterial chemoembolization combined with microwave ablation for unresectable hepatocellular carcinoma:a systematic review and meta-analysis[J].International Journal of Hyperthermia,2019,36(1):1288-1296.

    • [32] WU L,TSILIMIGRAS D I,FAROOQ A,et al.Potential survival benefit of radiofrequency ablation for small solitary intrahepatic cholangiocarcinoma in nonsurgically managed patients:a population-based analysis[J].J Surg Oncol,2019,120(8):1358-1364.

    • [33] BRANDI G,RIZZO A,DALL'OLIO F G,et al.Percutaneous radiofrequency ablation in intrahepatic cholangiocarcinoma:a retrospective single-center experience[J].International Journal of Hyperthermia,2020,37(1):479-485.

    • [34] MASSIRONI S,PILLA L,ELVEVI A,et al.New and emerging systemic therapeutic options for advanced cholangiocarcinoma[J].Cells,2020,9(3):688.

    • [35] LOUIS C,PAPOUTSOGLOU P,COULOUARN C.Molecular classification of cholangiocarcinoma[J].Curr Opin Gastroenterol,2020,36(2):57-62.

    • [36] JAVLE M,LOWERY M,SHROFF R T,et al.Phase Ⅱstudy of BGJ398 in patients with FGFR-altered advancedcholangiocarcinoma[J].J Clin Oncol,2018,36(3):276-282.

    • [37] MAZZAFERRO V,EL-RAYES B F,DROZ DIT BUSSET M,et al.Derazantinib(ARQ 087)in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma[J].Br J Cancer,2019,120(2):165-171.

    • [38] ABOU-ALFA G K,SAHAI V,HOLLEBECQUE A,et al.Pemigatinib for previously treated,locally advanced or metastatic cholangiocarcinoma:a multicentre,open-label,phase 2 study[J].Lancet Oncol,2020,21(5):671-684.

    • [39] GOYAL L,SHI L,LIU L Y,et al.TAS-120 overcomes resistance to ATP-competitive FGFR inhibitors in patients with FGFR2 fusion-positive intrahepatic cholangiocarcinoma[J].Cancer Discovery,2019,9(8):1064-1079.

    • [40] BORGER D R,TANABE K K,FAN K C,et al.Frequent mutation of isocitrate dehydrogenase(IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping[J].Oncologist,2012,17(1):72-79.

    • [41] LOWERY M A,BURRIS H A,JANKU F,et al.Safety and activity of ivosidenib in patients with IDH1-mutant advanced cholangiocarcinoma:a phase 1 study[J].The Lancet Gastroenterology & Hepatology,2019,4(9):711-720.

    • [42] ABOU-ALFA G K,MACARULLA T,JAVLE M M,et al.Ivosidenib in IDH1-mutant,chemotherapy-refractory cholangiocarcinoma(ClarIDHy):a multicentre,randomised,double-blind,placebo-controlled,phase 3 study[J].Lancet Oncol,2020,21(6):796-807.

    • [43] GALDY S,LAMARCA A,MCNAMARA M G,et al.HER2/HER3 pathway in biliary tract malignancies;systematic review and meta-analysis:a potential therapeutic target?[J].Cancer Metastasis Reviews,2017,36(1):141-157.

    • [44] RIZZO A,FREGA G,RICCI A D,et al.Anti-EGFR monoclonal antibodies in advanced biliary tract cancer:a systematic review and meta-analysis[J].In Vivo,2020,34(2):479-488.

    • [45] GOYAL L,ZHENG H,YURGELUN M B,et al.A phase 2 and biomarker study of cabozantinib in patients with advanced cholangiocarcinoma[J].Cancer,2017,123(11):1979-1988.

    • [46] LEE S H,LEE H S,LEE S H,et al.Efficacy and safety of pembrolizumab for gemcitabine/cisplatin-refractory biliary tract cancer:a multicenter retrospective study[J].Journal of Clinical Medicine,2020,9(6):1769.

    • [47] KANG J,JEONG J H,HWANG H S,et al.Efficacy and safety of pembrolizumab in patients with refractory advanced biliary tract cancer:tumor proportion score as a potential biomarker for response[J].Cancer Research and Treatment,2020,52(2):594-603.

    • [48] GOU M,ZHANG Y,SI H,et al.Efficacy and safety of nivolumab for metastatic biliary tract cancer[J].OncoTargets and Therapy,2019,12:861-867.

    • [49] UENO M,IKEDA M,MORIZANE C,et al.Nivolumab alone or in combination with cisplatin plus gemcitabine in Japanese patients with unresectable or recurrent biliary tract cancer:a non-randomised,multicentre,open-label,phase 1 study[J].The Lancet Gastroenterology & Hepatology,2019,4(8):611-621.

    • [50] KIM R D,CHUNG V,ALESE O B,et al.A Phase 2 multi-institutional study of nivolumab for patients with advanced refractory biliary tract cancer [J].JAMA Oncol,2020,6(6):888-894.

    • [51] SHEN L,GUO J,ZHANG Q,et al.Tislelizumab in Chinese patients with advanced solid tumors:an open-label,non-comparative,phase 1/2 study[J].Journal for Immunotherapy of Cancer,2020,8(1):e000437.

    • [52] DESAI J,DEVA S,LEE J S,et al.Phase IA/IB study of single-agent tislelizumab,an investigational anti-PD-1 antibody,in solid tumors[J].Journal for Immunotherapy of Cancer,2020,8(1):e000453.

    • [53] MOSER J C,PULIDO J S,DRONCA R S,et al.The Mayo Clinic experience with the use of kinase inhibitors,ipilimumab,bevacizumab,and local therapies in the treatment of metastatic uveal melanoma[J].Melanoma Research,2015,25(1):59-63.

    • [54] LIANG T Z,WHANG G,CHOPRA S.Primary hepatic carcinoma with inhibin positivity in a young male patient:a rare tumor previously only reported in females-case report and review of literature[J].Virchows Archiv,2020.

    • [55] INOZUME T,HANADA K,WANG Q J,et al.IL-17 secreted by tumor reactive T cells induces IL-8 release by human renal cancer cells[J].Journal of Immunotherapy,2009,32(2):109-117.

    • [56] KLEIN O,KEE D,NAGRIAL A,et al.Evaluation of combination nivolumab and ipilimumab immunotherapy in patients with advanced biliary tract cancers:subgroup analysis of a phase 2 nonrandomized clinical trial[J].JAMA Oncol,2020,6(9):1405-1409.

    • [57] 吴锦洪,周冬儿,于源泉,等.肝内胆管癌新辅助化疗后手术切除1例报告并文献复习[J].中国实用外科杂志,2017,37(7):818-820,822.

    • [58] 彭淑牖,王许安,黄从云,等.以实际解剖部位命名的分型法:对五种胆道疾病分型的思考[J].中华外科杂志,2019,57(6):412-417.

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