肝内胆管癌局部治疗及系统治疗研究进展

刘洋; 施祥德; 刘明奇; 刘超

doi:10.12449/JCH251203

肝内胆管癌局部治疗及系统治疗研究进展

DOI: 10.12449/JCH251203

刘洋¹,
施祥德²,
刘明奇²,
刘超^2, , ,

1.
贵州医科大学附属医院肝胆外科，贵阳 550000
2.
中山大学孙逸仙纪念医院胆胰外科，广州 510000

基金项目:

广州市科技计划项目 (2024A04J4776);

中山大学中央高校基本科研业务费专项资金临床研究5010计划资助 (2018008);

广州市临床重大技术建设项目 (2023P-ZD17)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：刘洋、施祥德负责设计并撰写论文；刘明奇负责对论文进行润色；刘超负责指导文章撰写并最后定稿。刘洋、施祥德对文章贡献等同，为共同第一作者。

详细信息

通信作者:
刘超， liuchao3@mail.sysu.edu.cn （ORCID： 0000-0001-6659-4372）

计量
- 文章访问数: 14
- HTML全文浏览量: 2
- PDF下载量: 6
- 被引次数: 0
出版历程
- 收稿日期: 2025-10-27
- 录用日期: 2025-11-20
- 出版日期: 2025-12-25

Research advances in local treatment and systemic therapy for intrahepatic cholangiocarcinoma

Yang LIU¹,
Xiangde SHI²,
Mingqi LIU²,
Chao LIU^{2
, ,
,}

1.
Department of Hepatobiliary Surgery，The Affiliated Hospital of Guizhou Medical University，Guiyang 550000，China
2.
Department of Biliary-Pancreatic Surgery，Sun Yat-sen Memorial Hospital，Sun Yat-sen University，Guangzhou 510000，China

Research funding:

Science and Technology Projects in Guangzhou (2024A04J4776);

Fundamental Research Funds for the Central Universities, Clinical Research 5010 Program,Sun Yat-sen University (2018008);

Major Clinical Technology Program of Guangzhou Municipal Health Commission (2023P-ZD17)

More Information

Corresponding author: LIU Chao， liuchao3@mail.sysu.edu.cn （ORCID： 0000-0001-6659-4372）

摘要

摘要: 肝内胆管癌（iCCA）是一种侵袭性强、预后极差的恶性肿瘤，近年来发病率逐年上升。本文简述了iCCA的主要局部治疗方式，并回顾了系统治疗的进展，重点评述了局部治疗联合靶向及免疫治疗的研究现状，分析其在提高客观缓解率、延长无进展生存期和总生存期方面的优势。文章指出，免疫联合化疗已成为不可切除iCCA的一线治疗标准，而局部治疗联合靶向免疫模式在早期研究中显示出更高的转化潜力和持久疗效。作者认为，未来应通过多中心、前瞻性研究进一步验证疗效与安全性，明确最佳联合模式与适应人群，为iCCA综合治疗提供新思路。
- 肝内胆管癌 /
- 局部治疗 /
- 系统治疗
Abstract: Intrahepatic cholangiocarcinoma （iCCA） is a highly aggressive malignant tumor with poor prognosis， and its incidence rate is gradually increasing in recent years. This article reviews the main local treatment methods for iCCA and the advances in related systemic therapies， with a focus on the current status of research on local treatment combined with targeted therapy and immunotherapy， highlighting their advantages in improving objective response rate and prolonging progression-free survival and overall survival. This article points out that immunotherapy combined with chemotherapy has become the first-line standard treatment for unresectable iCCA， while the regimen of local treatment combined with targeted therapy and immunotherapy has shown promising potential in clinical translation and sustained efficacy in early-phase studies. The authors believe that in the future， multicenter prospective studies are needed to verify the efficacy and safety of the above treatment regimen， determine the optimal combined treatment regimen， and define suitable patient populations， in order to provide new ideas for the comprehensive treatment of iCCA.
- IntrahepaticCholangiocarcinoma /
- Local Treatment /
- Systemic Therapy

HTML全文

表 1 HAIC联合靶向免疫治疗iCCA相关研究

Table 1. Research on HAIC combined with targeted therapy and immunotherapy for iCCA

作者（发表年）		疾病	样本量	ORR（%）	DCR（%）	mPFS（月）	mOS（月）	≥G3 AE
Lin^［67］（2024）	回顾性三队列；HLP： HAIC+仑伐替尼+PD- （L）1；SCP：系统化疗 +PD-（L）1；SC：化疗	iCCA	HLP：42 SCP：49 SC：50	50.0 vs 18.4 vs 6.0	88.1 vs 69.4 vs 46.0	30.0 vs 10.2 vs 6.5	NR vs NR vs 21.8	tHLP组≥G3~ 4 AE 更少
Xu^［68］（2025）	回顾性双臂；HAIC （FOLFOX/GEMOX）+ 仑伐替尼+PD-1 vs 系统化疗	iCCA	86（PSM 30/30）	56.7 vs 23.3	93.3 vs 70.0	11.17 vs 5.55	16.91 vs 11.06	两组相当
Zheng^［69］（2025）	回顾性双臂；FOLFOX- HAIC+TKI+PD-1 vs 系统化疗	iCCA	76 vs 76 （after PSM）	35.5 vs 14.5	76.3 vs 60.5	9.07 vs 6.23	20.77 vs 14.83	三联组ALT 升高较多
Huang^［70］（2024）	回顾性单臂；FOLFOX- HAIC+仑伐替尼+PD-1	iCCA	46	47.8 （mRECIST 56.5）	87.0	9.40	16.77	58.7%（ G3：47.8%， G4：10.9%）
Zhao^［71］（2024）	回顾性单臂；FOLFOX- HAIC+仑伐替尼 +durvalumab	iCCA	28	39.1 （mRECIST 65.2）	82.6	11.9	17.9	46.5%
Zhang^［72］（2022）	回顾性双臂；HAIC （FOLFOX/GEMOX） +TKI+PD-1 vs ALT+ TKI+PD-1	iCCA	39 vs 19	48.7 vs 15.8 （RECIST）； 61.5 vs 21.1 （mRECIST）	82.1 vs 36.8	NR （1年 PFS率 61.9% vs 31.6%）	—	差异无统计学意义
Cai^［74］（2025）	回顾性双臂；HLP： HAIC+仑伐替尼+PD- 1；SCLP：系统化疗+仑伐替尼+PD-1	iCCA	HLP：25 SCLP：28	52 vs 25	96.0 vs 78.6	8.8 vs 6.4	12.8 vs 11.0	HLP组≥G3~ 4 AE 更少
Wei^［75］（2023）	回顾性；FOLFOX- HAIC+仑伐替尼 ±PD-1	CCA （mixed）	35 vs 20	28.60	80	6.5 vs 3.5	16 vs 11	无显著差异； PD-1组2例 G5免疫相关肺炎
Li^［76］（2025）	多中心回顾性；（HAIC/ TACE/RT）+仑伐替尼 +ICI vs 化疗+ICI	iCCA	78 vs 70	51.3 vs 27.1	85.9 vs 81.4	10.8 vs 7.6	18.5 vs 15.0	60.3% vs 58.6%
Song^［77］（2025）	回顾性单臂；HAIC （mFOLFOX6）+托瑞帕利单抗+surufatinib	iCCA	28	57	79	9.5	—	21.42%
Lin^［78］（2024）	回顾性；FOLFOX- HAIC+仑伐替尼+PD- 1 vs GC （吉西他滨/ 顺铂）	iCCA	51 vs 39 （PSM 30/30）	43.1 vs 20.5	86.3 vs 66.7	12.0 vs 6.9	16.8 vs 11.0	系统化疗组 AE较高
Hu^［79］（2025）	回顾性；PSM 40/40；动脉FOLFOX（HAIC） +PD-（L）1 vs 系统化疗 +PD-（L）1	iCCA	182 （PSM 61/26）	50.8 vs 26.9	91.8 vs 84.6	10.4 vs 6.4	14.5 vs 10.5	49.2% vs 46.2%
Li^［80］（2025）	多中心回顾性；LRT （HAIC/TACE/RT） +GEMOX（≥2周期）+ 仑伐替尼+ICI	iCCA	47	61.7	93.6	10.2	20.2	66.0%
注：HAIC，经导管肝动脉灌注化疗；iCCA，肝内胆管癌；ORR，客观缓解率；DCR，疾病控制率；PFS，无进展生存期；mOS，中位总生存期；AE，不良事件；PD-1，程序性死亡受体1；PD-L1，程序性死亡配体1；PSM，倾向评分匹配；TKI，酪氨酸激酶抑制剂；ICI，免疫检查点抑制剂；—，未报告。

下载: 导出CSV

参考文献(82)

[1]	SIEGEL RL, MILLER KD, FUCHS HE, et al. Cancer statistics, 2022[J]. CA A Cancer J Clin, 2022, 72( 1): 7- 33. DOI: 10.3322/caac.21708.
[2]	BEAL EW, TUMIN D, MORIS D, et al. Cohort contributions to trends in the incidence and mortality of intrahepatic cholangiocarcinoma[J]. Hepatobiliary Surg Nutr, 2018, 7( 4): 270- 276. DOI: 10.21037/hbsn.2018.03.16.
[3]	SAHA SK, ZHU AX, FUCHS CS, et al. Forty-year trends in cholangiocarcinoma incidence in the U.S.: Intrahepatic disease on the rise[J]. Oncologist, 2016, 21( 5): 594- 599. DOI: 10.1634/theoncologist.2015-0446.
[4]	FLORIO AA, FERLAY J, ZNAOR A, et al. Global trends in intrahepatic and extrahepatic cholangiocarcinoma incidence from 1993 to 2012[J]. Cancer, 2020, 126( 11): 2666- 2678. DOI: 10.1002/cncr.32803.
[5]	ENDO I, GONEN M, YOPP AC, et al. Intrahepatic cholangiocarcinoma: Rising frequency, improved survival, and determinants of outcome after resection[J]. Ann Surg, 2008, 248( 1): 84- 96. DOI: 10.1097/sla.0b013e318176c4d3.
[6]	EL-DIWANY R, PAWLIK TM, EJAZ A. Intrahepatic cholangiocarcinoma[J]. Surg Oncol Clin N Am, 2019, 28( 4): 587- 599. DOI: 10.1016/j.soc.2019.06.002.
[7]	MORIS D, PALTA M, KIM C, et al. Advances in the treatment of intrahepatic cholangiocarcinoma: An overview of the current and future therapeutic landscape for clinicians[J]. CA A Cancer J Clin, 2023, 73( 2): 198- 222. DOI: 10.3322/caac.21759.
[8]	BENSON AB, D’ANGELICA MI, ABRAMS T, et al. NCCN Guidelines^® Insights: Biliary tract cancers, version 2.2023[J]. J Natl Compr Canc Netw, 2023, 21( 7): 694- 704. 10.6004/jnccn.2023.0035. DOI: 10.6004/jnccn.2023.0035
[9]	YUAN P, SONG JH, WANG F, et al. Combination of TACE and Lenvatinib as a promising option for downstaging to surgery of initially unresectable intrahepatic cholangiocarcinoma[J]. Investig New Drugs, 2022, 40( 5): 1125- 1132. DOI: 10.1007/s10637-022-01257-z.
[10]	YANG XG, SUN YY, LI DS, et al. Efficacy and safety of drug-eluting beads transarterial chemoembolization combining immune checkpoint inhibitors in unresectable intrahepatic cholangiocarcinoma: A propensity score matching analysis[J]. Front Immunol, 2022, 13: 940009. DOI: 10.3389/fimmu.2022.940009.
[11]	GEORGIADES CS, HONG K, GESCHWIND JF. Radiofrequency ablation and chemoembolization for hepatocellular carcinoma[J]. Cancer J, 2008, 14( 2): 117- 122. DOI: 10.1097/ppo.0b013e31816a0fac.
[12]	KIEFER MV, ALBERT M, MCNALLY M, et al. Chemoembolization of intrahepatic cholangiocarcinoma with cisplatinum, doxorubicin, mitomycin C, ethiodol, and polyvinyl alcohol: A 2-center study[J]. Cancer, 2011, 117( 7): 1498- 1505. DOI: 10.1002/cncr.25625.
[13]	KIM JH, YOON HK, SUNG KB, et al. Transcatheter arterial chemoembolization or chemoinfusion for unresectable intrahepatic cholangiocarcinoma: Clinical efficacy and factors influencing outcomes[J]. Cancer, 2008, 113( 7): 1614- 1622. DOI: 10.1002/cncr.23787.
[14]	VOGL TJ, NAGUIB NNN, NOUR-ELDIN NA, 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. DOI: 10.1002/ijc.26407.
[15]	PARK SY, KIM JH, YOON HJ, et al. Transarterial chemoembolization versus supportive therapy in the palliative treatment of unresectable intrahepatic cholangiocarcinoma[J]. Clin Radiol, 2011, 66( 4): 322- 328. DOI: 10.1016/j.crad.2010.11.002.
[16]	AYYUB J, DABHI KN, GOHIL NV, et al. Evaluation of the safety and efficacy of conventional transarterial chemoembolization(cTACE) and drug-eluting bead(DEB)-TACE in the management of unresectable hepatocellular carcinoma: A systematic review[J]. Cureus, 2023, 15( 7): e41943. DOI: 10.7759/cureus.41943.
[17]	TANG JJ, HUANG ZL, XU JC, et al. Drug-eluting bead transarterial chemoembolization(TACE) exhibits superior efficacy and equal tolerance to conventional TACE in hepatocellular carcinoma patients with conventional TACE history[J]. Clin Res Hepatol Gastroenterol, 2022, 46( 3): 101814. DOI: 10.1016/j.clinre.2021.101814.
[18]	KUHLMANN JB, EURINGER W, SPANGENBERG HC, 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. DOI: 10.1097/meg.0b013e3283502241.
[19]	WANG JX, XUE YQ, LIU R, et al. DEB-TACE with irinotecan versus C-TACE for unresectable intrahepatic cholangiocarcinoma: A prospective clinical study[J]. Front Bioeng Biotechnol, 2023, 10: 1112500. DOI: 10.3389/fbioe.2022.1112500.
[20]	SCHARTZ DA, PORTER M, SCHARTZ E, et al. Transarterial yttrium-90 radioembolization for unresectable intrahepatic cholangiocarcinoma: A systematic review and meta-analysis[J]. J Vasc Interv Radiol, 2022, 33( 6): 679- 686. DOI: 10.1016/j.jvir.2022.02.016.
[21]	EDELINE J, LAMARCA A, MCNAMARA MG, et al. Locoregional therapies in patients with intrahepatic cholangiocarcinoma: A systematic review and pooled analysis[J]. Cancer Treat Rev, 2021, 99: 102258. DOI: 10.1016/j.ctrv.2021.102258.
[22]	BOEHM LM, JAYAKRISHNAN TT, MIURA JT, et al. Comparative effectiveness of hepatic artery based therapies for unresectable intrahepatic cholangiocarcinoma: hepatic artery therapy for unresectable ICC[J]. J Surg Oncol, 2015, 111( 2): 213- 220. DOI: 10.1002/jso.23781.
[23]	KEMENY NE, SCHWARTZ L, GÖNEN M, et al. Treating primary liver cancer with hepatic arterial infusion of floxuridine and dexamethasone: Does the addition of systemic bevacizumab improve results[J]. Oncology, 2011, 80( 3-4): 153- 159. DOI: 10.1159/000324704.
[24]	CERCEK A, BOERNER T, TAN BR, et al. Assessment of hepatic arterial infusion of floxuridine in combination with systemic gemcitabine and oxaliplatin in patients with unresectable intrahepatic cholangiocarcinoma: A phase 2 clinical trial[J]. JAMA Oncol, 2020, 6( 1): 60. DOI: 10.1001/jamaoncol.2019.3718.
[25]	JARNAGIN WR, SCHWARTZ LH, GULTEKIN DH, et al. Regional chemotherapy for unresectable primary liver cancer: Results of a phase II clinical trial and assessment of DCE-MRI as a biomarker of survival[J]. Ann Oncol, 2009, 20( 9): 1589- 1595. DOI: 10.1093/annonc/mdp029.
[26]	JOLISSAINT JS, SOARES KC, SEIER KP, et al. Intrahepatic cholangiocarcinoma with lymph node metastasis: Treatment-related outcomes and the role of tumor genomics in patient selection[J]. Clin Cancer Res, 2021, 27( 14): 4101- 4108. DOI: 10.1158/1078-0432.ccr-21-0412.
[27]	CHIOU YY, HWANG JI, CHOU YH, et al. Percutaneous ultrasound-guided radiofrequency ablation of intrahepatic cholangiocarcinoma[J]. The Kaohsiung J Med Scie, 2005, 21( 7): 304- 309. DOI: 10.1016/s1607-551x(09)70125-1.
[28]	MORIZANE C, OKUSAKA T, MIZUSAWA J, et al. Combination gemcitabine plus S-1 versus gemcitabine plus cisplatin for advanced/recurrent biliary tract cancer: The FUGA-BT(JCOG1113) randomized phase III clinical trial[J]. Ann Oncol, 2019, 30( 12): 1950- 1958. DOI: 10.1093/annonc/mdz402.
[29]	IOKA T, KANAI M, KOBAYASHI S, et al. Randomized phase III study of gemcitabine, cisplatin plus S-1 versus gemcitabine, cisplatin for advanced biliary tract cancer(KHBO1401- MITSUBA)[J]. J Hepato Biliary Pancreat, 2023, 30( 1): 102- 110. DOI: 10.1002/jhbp.1219.
[30]	SHROFF RT, KING G, COLBY S, et al. SWOG S1815: A phase III randomized trial of gemcitabine, cisplatin, and nab-paclitaxel versus gemcitabine and cisplatin in newly diagnosed, advanced biliary tract cancers[J]. J Clin Oncol, 2025, 43( 5): 536- 544. DOI: 10.1200/jco-24-01383.
[31]	PHELIP JM, DESRAME J, EDELINE J, et al. Modified FOLFIRINOX versus CISGEM chemotherapy for patients with advanced biliary tract cancer(PRODIGE 38 AMEBICA): A randomized phase II study[J]. J Clin Oncol, 2022, 40( 3): 262- 271. DOI: 10.1200/jco.21.00679.
[32]	AITCHESON G, MAHIPAL A, JOHN BV. Targeting FGFR in intrahepatic cholangiocarcinoma[iCCA]: Leading the way for precision medicine in biliary tract cancer[BTC]?[J]. Expert Opin Investig Drugs, 2021, 30( 4): 463- 477. DOI: 10.1080/13543784.2021.1900821.
[33]	KENDRE G, MURUGESAN K, BRUMMER T, et al. Charting co-mutation patterns associated with actionable drivers in intrahepatic cholangiocarcinoma[J]. J Hepatol, 2023, 78( 3): 614- 626. DOI: 10.1016/j.jhep.2022.11.030.
[34]	BABINA IS, TURNER NC. Advances and challenges in targeting FGFR signalling in cancer[J]. Nat Rev Cancer, 2017, 17( 5): 318- 332. DOI: 10.1038/nrc.2017.8.
[35]	ABOU-ALFA GK, 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. DOI: 10.1016/s1470-2045(20)30109-1.
[36]	VOGEL A, SAHAI V, HOLLEBECQUE A, et al. An open-label study of pemigatinib in cholangiocarcinoma: Final results from FIGHT-202[J]. ESMO Open, 2024, 9( 6): 103488. DOI: 10.1016/j.esmoop.2024.103488.
[37]	RIZZO A, RICCI AD, BRANDI G. IDH inhibitors in advanced cholangiocarcinoma: Another arrow in the quiver?[J]. Cancer Treat Res Commun, 2021, 27: 100356. DOI: 10.1016/j.ctarc.2021.100356.
[38]	LIN JZ, CAO YH, YANG X, et al. Mutational spectrum and precision oncology for biliary tract carcinoma[J]. Theranostics, 2021, 11( 10): 4585- 4598. DOI: 10.7150/thno.56539.
[39]	LAVACCHI D, CALIMAN E, ROSSI G, et al. Ivosidenib in IDH1-mutated cholangiocarcinoma: Clinical evaluation and future directions[J]. Pharmacol Ther, 2022, 237: 108170. DOI: 10.1016/j.pharmthera.2022.108170.
[40]	ABOU-ALFA GK, MACARULLA T, JAVLE MM, 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. DOI: 10.1016/s1470-2045(20)30157-1.
[41]	ZHU AX, MACARULLA T, JAVLE MM, et al. Final overall survival efficacy results of ivosidenib for patients with advanced cholangiocarcinoma with IDH1 mutation: The phase 3 randomized clinical ClarIDHy trial[J]. JAMA Oncol, 2021, 7( 11): 1669. DOI: 10.1001/jamaoncol.2021.3836.
[42]	GALDY S, LAMARCA A, MCNAMARA MG, et al. HER2/HER3 pathway in biliary tract malignancies; systematic review and meta-analysis: A potential therapeutic target?[J]. Cancer Metastasis Rev, 2017, 36( 1): 141- 157. DOI: 10.1007/s10555-016-9645-x.
[43]	PU XH, LI L, XU F, et al. HER2 amplification subtype intrahepatic cholangiocarcinoma exhibits high mutation burden and T cell exhaustion microenvironment[J]. J Cancer Res Clin Oncol, 2024, 150( 8): 403. DOI: 10.1007/s00432-024-05894-0.
[44]	JAVLE M, BORAD MJ, AZAD NS, et al. Pertuzumab and trastuzumab for HER2-positive, metastatic biliary tract cancer(MyPathway): A multicentre, open-label, phase 2a, multiple basket study[J]. Lancet Oncol, 2021, 22( 9): 1290- 1300. DOI: 10.1016/s1470-2045(21)00336-3.
[45]	KUDO M, FINN RS, QIN SK, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: A randomised phase 3 non-inferiority trial[J]. Lancet, 2018, 391( 10126): 1163- 1173. DOI: 10.1016/s0140-6736(18)30207-1.
[46]	ZHAO Y, ZHANG YN, WANG KT, et al. Lenvatinib for hepatocellular carcinoma: From preclinical mechanisms to anti-cancer therapy[J]. Biochim Biophys Acta BBA Rev Cancer, 2020, 1874( 1): 188391. DOI: 10.1016/j.bbcan.2020.188391.
[47]	SCHLUMBERGER M, TAHARA M, WIRTH LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer[J]. N Engl J Med, 2015, 372( 7): 621- 630. DOI: 10.1056/nejmoa1406470.
[48]	UENO M, IKEDA M, SASAKI T, et al. Phase 2 study of lenvatinib monotherapy as second-line treatment in unresectable biliary tract cancer: Primary analysis results[J]. BMC Cancer, 2020, 20( 1): 1105. DOI: 10.1186/s12885-020-07365-4.
[49]	SHI GM, HUANG XY, WU D, et al. Toripalimab combined with lenvatinib and GEMOX is a promising regimen as first-line treatment for advanced intrahepatic cholangiocarcinoma: A single-center, single-arm, phase 2 study[J]. Sig Transduct Target Ther, 2023, 8: 106. DOI: 10.1038/s41392-023-01317-7.
[50]	PIHA-PAUL SA, OH DY, UENO M, et al. Efficacy and safety of pembrolizumab for the treatment of advanced biliary cancer: Results from the KEYNOTE-158 and KEYNOTE-028 studies[J]. Int J Cancer, 2020, 147( 8): 2190- 2198. DOI: 10.1002/ijc.33013.
[51]	KIM RD, CHUNG V, ALESE OB, 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. DOI: 10.1001/jamaoncol.2020.0930.
[52]	MELERO I, YAU T, KANG YK, et al. Nivolumab plus ipilimumab combination therapy in patients with advanced hepatocellular carcinoma previously treated with sorafenib: 5-year results from CheckMate 040[J]. Ann Oncol, 2024, 35( 6): 537- 548. DOI: 10.1016/j.annonc.2024.03.005.
[53]	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. DOI: 10.1001/jamaoncol.2020.2814.
[54]	SAHAI V, GRIFFITH KA, BEG MS, et al. A randomized phase 2 trial of nivolumab, gemcitabine, and cisplatin or nivolumab and ipilimumab in previously untreated advanced biliary cancer: BilT-01[J]. Cancer, 2022, 128( 19): 3523- 3530. DOI: 10.1002/cncr.34394.
[55]	OH DY, RUTH HE A, QIN SK, et al. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer[J]. NEJM Evid, 2022, 1( 8): EVIDoa2200015. DOI: 10.1056/evidoa2200015.
[56]	KELLEY R K, UENO M, YOO C, et al. Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer(KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial[J]. Lancet, 2023, 401( 10391): 1853- 1865. DOI: 10.1016/s0140-6736(23)00727-4.
[57]	ZHONG BY, FAN WZ, GUAN JJ, et al. Combination locoregional and systemic therapies in hepatocellular carcinoma[J]. Lancet Gastroenterol Hepatol, 2025, 10( 4): 369- 386. DOI: 10.1016/s2468-1253(24)00247-4.
[58]	KIM DH. Combination of interventional oncology local therapies and immunotherapy for the treatment of hepatocellular carcinoma[J]. J Liver Cancer, 2022, 22( 2): 93- 102. DOI: 10.17998/jlc.2022.03.28.
[59]	PINATO DJ, MURRAY SM, FORNER A, et al. Trans-arterial chemoembolization as a loco-regional inducer of immunogenic cell death in hepatocellular carcinoma: Implications for immunotherapy[J]. J Immunother Cancer, 2021, 9( 9): e003311. DOI: 10.1136/jitc-2021-003311.
[60]	TAKAKI H, IMAI N, CONTESSA TT, et al. Peripheral blood regulatory T-cell and type 1 helper T-cell population decrease after hepatic artery embolization[J]. J Vasc Interv Radiol, 2016, 27( 10): 1561- 1568. DOI: 10.1016/j.jvir.2016.01.150.
[61]	HICKEY RM, KULIK LM, NIMEIRI H, et al. Immuno-oncology and its opportunities for interventional radiologists: Immune checkpoint inhibition and potential synergies with interventional oncology procedures[J]. J Vasc Interv Radiol, 2017, 28( 11): 1487- 1494. DOI: 10.1016/j.jvir.2017.07.018.
[62]	LIU WM, FOWLER DW, SMITH P, et al. Pre-treatment with chemotherapy can enhance the antigenicity and immunogenicity of tumours by promoting adaptive immune responses[J]. Br J Cancer, 2010, 102( 1): 115- 123. DOI: 10.1038/sj.bjc.6605465.
[63]	MEI ZB, GAO XX, PAN CX, et al. Lenvatinib enhances antitumor immunity by promoting the infiltration of TCF1⁺CD8⁺ T cells in HCC via blocking VEGFR2[J]. Cancer Sci, 2023, 114( 4): 1284- 1296. DOI: 10.1111/cas.15719.
[64]	TORRENS L, MONTIRONI C, PUIGVEHÍ M, et al. Immunomodulatory effects of lenvatinib plus anti-programmed cell death protein 1 in mice and rationale for patient enrichment in hepatocellular carcinoma[J]. Hepatology, 2021, 74( 5): 2652- 2669. DOI: 10.1002/hep.32023.
[65]	YAMAUCHI M, ONO A, AMIOKA K, et al. Lenvatinib activates anti-tumor immunity by suppressing immunoinhibitory infiltrates in the tumor microenvironment of advanced hepatocellular carcinoma[J]. Commun Med, 2023, 3: 152. DOI: 10.1038/s43856-023-00390-x.
[66]	YANG JY, GUO ZX, SONG MJ, et al. Lenvatinib improves anti-PD-1 therapeutic efficacy by promoting vascular normalization via the NRP-1-PDGFRβ complex in hepatocellular carcinoma[J]. Front Immunol, 2023, 14: 1212577. DOI: 10.3389/fimmu.2023.1212577.
[67]	LIN YS, LI S, YANG X, et al. First-line hepatic arterial infusion chemotherapy plus lenvatinib and PD-(L)₁ inhibitors versus systemic chemotherapy alone or with PD-(L)₁ inhibitors in unresectable intrahepatic cholangiocarcinoma[J]. J Cancer Res Clin Oncol, 2024, 150( 6): 309. DOI: 10.1007/s00432-024-05795-2.
[68]	XU QY, WANG CD, YOU R, et al. Hepatic arterial infusion chemotherapy(HAIC) plus Lenvatinib and PD-1 inhibitors versus systemic chemotherapy for unresectable intrahepatic cholangiocarcinoma[J]. Discov Oncol, 2025, 16( 1): 775. DOI: 10.1007/s12672-025-02397-3.
[69]	ZHENG ZK, WANG JL, WU TQ, et al. Hepatic arterial infusion chemotherapy plus targeted therapy and immunotherapy versus systemic chemotherapy for advanced intrahepatic cholangiocarcinoma: A retrospective cohort study[J]. Int J Surg, 2025, 111( 1): 1552- 1557. DOI: 10.1097/js9.0000000000002013.
[70]	HUANG YX, DU ZF, KAN AN, et al. Clinical and biomarker analyses of hepatic arterial infusion chemotherapy plus lenvatinib and PD-1 inhibitor for patients with advanced intrahepatic cholangiocarcinoma[J]. Front Immunol, 2024, 15: 1260191. DOI: 10.3389/fimmu.2024.1260191.
[71]	ZHAO RC, ZHOU J, MIAO ZX, et al. Efficacy and safety of lenvatinib plus durvalumab combined with hepatic arterial infusion chemotherapy for unresectable intrahepatic cholangiocarcinoma[J]. Front Immunol, 2024, 15: 1397827. DOI: 10.3389/fimmu.2024.1397827.
[72]	ZHANG N, YU BR, WANG YX, et al. Clinical outcomes of hepatic arterial infusion chemotherapy combined with tyrosine kinase inhibitors and anti-PD-1 immunotherapy for unresectable intrahepatic cholangiocarcinoma[J]. J Dig Dis, 2022, 23( 8-9): 535- 545. DOI: 10.1111/1751-2980.13127.
[73]	LI KS, ZHANG TZ, GAO Q, et al. HAIC plus TAE combined with tislelizumab and surufatinib in unresectable intrahepatic cholangiocarcinoma: The REACH-01 trial[J]. J Clin Oncol, 2025, 43( 16_suppl): 4087. DOI: 10.1200/jco.2025.43.16_suppl.4087.
[74]	CAI YX, WEN W, XIA YS, et al. The efficacy and safety of hepatic artery infusion chemotherapy combined with lenvatinib and programmed death(PD)-1 inhibitors for unresectable intrahepatic cholangiocarcinoma: A retrospective study[J]. Curr Oncol, 2025, 32( 2): 87. DOI: 10.3390/curroncol32020087.
[75]	WEI ZQ, WANG YJ, WU BY, et al. Hepatic arterial infusion chemotherapy plus lenvatinib with or without programmed cell death protein-1 inhibitors for advanced cholangiocarcinoma[J]. Front Immunol, 2023, 14: 1235724. DOI: 10.3389/fimmu.2023.1235724.
[76]	LI SF, YU GH, WANG MM, et al. Local-regional therapy combined with immune checkpoint inhibitors and lenvatinib versus immune checkpoint inhibitors plus chemotherapy in advanced intrahepatic cholangiocarcinoma: A multicenter cohort study[J]. Cancer Immunol Immunother, 2025, 74( 8): 271. DOI: 10.1007/s00262-025-04129-6.
[77]	SONG SL, LIU YM, REN YQ, et al. Hepatic arterial infusion chemotherapy combined with toripalimab and surufatinib for the treatment of advanced intrahepatic cholangiocarcinoma[J]. Diagn Interv Radiol, 2025, 31( 2): 145- 151. DOI: 10.4274/dir.2024.242673.
[78]	LIN ZP, ZOU XG, HU XL, et al. Efficacy analysis of HAIC combined with lenvatinib plus PD-1 inhibitor vs. first-line systemic chemotherapy for advanced intrahepatic cholangiocarcinoma[J]. Sci Rep, 2024, 14: 23961. DOI: 10.1038/s41598-024-75102-z.
[79]	HU Y, JIANG XY, CAI X, et al. Efficacy and safety of arterial FOLFOX chemotherapy plus anti-PD-(L)₁ immunotherapy as a first-line treatment for unresectable intrahepatic cholangiocarcinoma: A propensity score matching analysis[J]. J Gastrointest Oncol, 2025, 16( 1): 209- 225. DOI: 10.21037/jgo-24-552.
[80]	LI SF, YU GH, WANG MM, et al. Efficacy and safety of local–regional therapy combined with chemotherapy, immune checkpoint inhibitors and lenvatinib as first-line treatment in advanced intrahepatic cholangiocarcinoma: A multicenter retrospective cohort study[J]. Cancer Immunol Immunother, 2025, 74( 7): 229. DOI: 10.1007/s00262-025-04085-1.
[81]	LIU S, WANG QD, YIN SH, et al. Efficacy analysis of drug-eluting beads transcatheter arterial chemoembolization combining systemic chemotherapy and immune checkpoint inhibitors in unresectable intrahepatic cholangiocarcinoma: A multicenter retrospective cohort study based on propensity score matching[J]. World J Surg Oncol, 2025, 23( 1): 21. DOI: 10.1186/s12957-025-03679-4.
[82]	HUANG JT, HU D, HONG X, et al. Effectiveness and safety of transarterial chemoembolization combined with PD-1 inhibitors and lenvatinib for unresectable intrahepatic cholangiocarcinoma[J]. Eur Radiol Exp, 2025, 9( 1): 21. DOI: 10.1186/s41747-025-00563-4.