不可切除肝内胆管癌的治疗方法研究进展

摘要/Abstract

摘要： 肝内胆管癌（ICC）是肝脏内第2常见原发性肿瘤,根治性手术切除是目前治愈ICC的主要方式,但ICC起病隐匿,进展迅速,临床发现时很多已经失去根治性手术的机会。临床常使用吉西他滨联合顺铂等化疗方案治疗不可切除的ICC,但疗效常不理想。靶向治疗、免疫治疗等新疗法的出现为治疗不可切除的ICC带来了新的方向。通过对ICC肿瘤发生机制的研究,研究人员发现了治疗ICC的潜在靶点,针对EGFR、VEGF、FGFR2、HER2、IDH1/2、BRAF、NTRK、MEK1/2等靶点的临床药物试验均已取得良好进展;免疫检查点抑制剂的试验也表现出对ICC患者的良好疗效。联合使用上述疗法还能使部分患者实现肿瘤降期,获得手术机会。本文综述了近年不可切除的ICC的治疗方法研究进展,以期为ICC治疗提供新思路。

关键词: 肝内胆管癌, 化学治疗, 分子靶向治疗, 免疫治疗

Abstract: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary tumor in the liver, and radical surgical resection is currently the main way to cure ICC. But ICC has an insidious onset, rapid progression, and many have lost the opportunity for radical surgery when clinically found. Chemotherapy regimens such as gemcitabine combined with cisplatin are often used clinically to treat unresectable ICC, but the efficacy is often not satisfactory. The emergence of new therapies such as targeted therapy and immunotherapy has brought a new direction for the treatment of unresectable ICC. Through the study of the mechanism of ICC tumorigenesis, researchers have discovered potential targets for the treatment of ICC, and clinical drug trials for targets such as EGFR, VEGF, FGFR2, HER2, IDH1/2, BRAF, NTRK, MEK1/2 and other targets have made good progress. Trials of immune checkpoint inhibitors have also shown good efficacy in patients with ICC. The combination of the above therapies can also enable some patients to achieve tumor reduction and obtain surgical opportunities. This article reviews the recent research progress of treatment for unresectable ICC, in order to provide new ideas for the treatment of ICC.

Key words: Intrahepatic cholangiocarcinoma, Chemotherapy, Molecularly targeted therapy, Immunotherapy

张永琪, 李照. 不可切除肝内胆管癌的治疗方法研究进展[J]. 肝癌电子杂志, 2024, 11(2): 89-93.

Zhang Yongqi, Li Zhao. Research progress in the treatment of unresectable intrahepatic cholangiocarcinoma[J]. Electronic Journal of Liver Tumor, 2024, 11(2): 89-93.

参考文献

[1] FLORIO A A, 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.
[2] ZENG W, MAO R, ZHANG Z, et al.Combination therapies for advanced biliary tract cancer[J]. J Clin Transl Hepatol, 2023, 11(2): 490-501.
[3] WEIGT J, MALFERTHEINER P.Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer[J]. Exp Rev Gastroenterol Hepatol, 2010, 4(4): 395-397.
[4] OKUSAKA T, NAKACHI K, FUKUTOMI A, et al.Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: a comparative multicentre study in japan[J]. Br J Cancer, 2010, 103(4): 469-474.
[5] ANDRÉ T, TOURNIGAND C, ROSMORDUC O, et al.Gemcitabine combined with oxaliplatin (GEMOX) in advanced biliary tract adenocarcinoma: a gercor study[J]. Ann Oncol, 2004, 15(9): 1339-1343.
[6] 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.
[7] SAHAI V, CATALANO P J, ZALUPSKI M M, et al.Nab-paclitaxel and gemcitabine as first-line treatment of advanced or metastatic cholangiocarcinoma: a phase 2 clinical trial[J]. JAMA Oncol, 2018, 4(12): 1707-1712.
[8] 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.
[9] KIM S T, KANG J H, LEE J, et al.Capecitabine plus oxaliplatin versus gemcitabine plus oxaliplatin as first-line therapy for advanced biliary tract cancers: a multicenter, open-label, randomized, phase Ⅲ, noninferiority trial[J]. Ann Oncol, 2019, 30(5): 788-795.
[10] 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 Hepatobiliary Pancreat Sci, 2023, 30(1): 102-110.
[11] LAMARCA A, PALMER D H, WASAN H S, et al.Second-line folfox chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial[J]. Lancet Oncol, 2021, 22(5): 690-701.
[12] YOO C, KIM K P, JEONG J H, et al.Liposomal irinotecan plus fluorouracil and leucovorin versus fluorouracil and leucovorin for metastatic biliary tract cancer after progression on gemcitabine plus cisplatin (NIFTY): a multicentre, open-label, randomised, phase 2b study[J]. Lancet Oncol, 2021, 22(11): 1560-1572.
[13] ZHENG Y, TU X, ZHAO P, et al.A randomised phase Ⅱ study of second-line xeliri regimen versus irinotecan monotherapy in advanced biliary tract cancer patients progressed on gemcitabine and cisplatin[J]. Br J Cancer, 2018, 119(3): 291-295.
[14] GUION-DUSSERRE J F, LORGIS V, VINCENT J, et al. FOLFIRI plus bevacizumab as a second-line therapy for metastatic intrahepatic cholangiocarcinoma[J]. World J Gastroenterol, 2015, 21(7): 2096-2101.
[15] PARK B K, PAIK Y H, PARK J Y, et al.The clinicopathologic significance of the expression of vascular endothelial growth factor-c in intrahepatic cholangiocarcinoma[J]. Am J Clin Oncol, 2006, 29(2): 138-142.
[16] DEMOLS A, BORBATH I, VAN DEN EYNDE M, et al. Regorafenib after failure of gemcitabine and platinum-based chemotherapy for locally advanced/metastatic biliary tumors: reachin, a randomized, double-blind, phase Ⅱ trial[J]. Ann Oncol, 2020, 31(9): 1169-1177.
[17] SUN W, PATEL A, NORMOLLE D, et al.A phase 2 trial of regorafenib as a single agent in patients with chemotherapy-refractory, advanced, and metastatic biliary tract adenocarcinoma[J]. Cancer, 2019, 125(6): 902-909.
[18] LEE S, SHROFF R T, MAKAWITA S, et al.Phase Ⅱ study of ramucirumab in advanced biliary tract cancer previously treated by gemcitabine-based chemotherapy[J]. Clin Cancer Res, 2022, 28(11): 2229-2236.
[19] LEE J, PARK S H, CHANG H M, et al.Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract cancer: a multicentre, open-label, randomised, phase 3 study[J]. Lancet Oncol, 2012, 13(2): 181-188.
[20] SJ L, MR M, JL K, et al.Report of a multicenter phase Ⅱ trial testing a combination of biweekly bevacizumab and daily erlotinib in patients with unresectable biliary cancer: a phase Ⅱ consortium study[J]. J Clin Oncol, 2010, 28(21): 3491-3497.
[21] BEKAII-SAAB T, PHELPS M A, LI X, et al.Multi-institutional phase Ⅱ study of selumetinib in patients with metastatic biliary cancers[J]. J Clin Oncol, 2011, 29(17): 2357-2363.
[22] ROSS J S, WANG K, GAY L, et al.New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing[J]. Oncologist, 2014, 19(3): 235-242.
[23] DRILON A, LAETSCH T W, KUMMAR S, et al.Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children[J]. N Engl J Med, 2018, 378(8): 731-739.
[24] 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.
[25] BIBEAU K, F?LIZ L, LIHOU C F, et al. Progression-free survival in patients with cholangiocarcinoma with or without FGF/FGFR alterations: a fight-202 post hoc analysis of prior systemic therapy response[J]. JCO Precis Oncol, 2022, 6: e2100414.
[26] JAVLE M M, ROYCHOWDHURY S, KELLEY R K, et al.Final results from a phase Ⅱ study of infigratinib (BGJ398), an FGFR-selective tyrosine kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma harboring an FGFR2 gene fusion or rearrangement[J]. J Clin Oncol, 2021, 39(3 Suppl): 265-265.
[27] GOYAL L, MERIC-BERNSTAM F, HOLLEBECQUE A, et al.Futibatinib for fgfr2-rearranged intrahepatic cholangiocarcinoma[J]. N Engl J Med, 2023, 388(3): 228-239.
[28] 王英珍, 曾也婷, 王心睿,等. 肝内和肝外胆管癌的分子改变及靶向治疗[J]. 临床与实验病理学杂志, 2022, 38(1): 65-68.
[29] CASAK S J, PRADHAN S, FASHOYIN-AJE L A, et al. FDA approval summary: ivosidenib for the treatment of patients with advanced unresectable or metastatic, chemotherapy refractory cholangiocarcinoma with an idh1 mutation[J]. Clin Cancer Res, 2022, 28(13): 2733-2737.
[30] SUBBIAH V, LASSEN U, ?LEZ E, et al. Dabrafenib plus trametinib in patients with BRAFV600e-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial[J]. Lancet Oncol, 2020, 21(9): 1234-1243.
[31] OHBA A, MORIZANE C, KAWAMOTO Y, et al.Trastuzumab deruxtecan (T-DXD; ds-8201) in patients (PTS) with HER2-expressing unresectable or recurrent biliary tract cancer (BTC): an investigator-initiated multicenter phase 2 study (HERB trial)[J]. J Clin Onco, 2022, 40(16 Suppl): 4006-4006.
[32] 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.
[33] PIHA-PAUL S A, OH D Y, 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.
[34] VILLANUEVA L, LWIN Z, CHUNG H C, et al.Lenvatinib plus pembrolizumab for patients with previously treated biliary tract cancers in the multicohort phase ii leap-005 study[J]. J Clin Oncol, 2021, 39(3 Suppl): 321-321.
[35] LIN J, YANG X, LONG J, et al.Pembrolizumab combined with lenvatinib as non-first-line therapy in patients with refractory biliary tract carcinoma[J]. Hepatobiliary Surg Nutr, 2020, 9(4): 414-424.
[36] JIAN Z, FAN J, SHI G-M, et al.Lenvatinib plus toripalimab as first-line treatment for advanced intrahepatic cholangiocarcinoma: a single-arm, phase 2 tria[J]. J Clin Oncol, 2021, 39(15 Suppl): 4099-4099.
[37] COUSIN S, BELLERA C A, GU?GAN J P, et al. Regomune: a phase Ⅱ study of regorafenib + avelumab in solid tumors—results of the biliary tract cancer (BTC) cohort[J]. J Clin Oncol, 2021, 39(15 Suppl): 4096-4096.
[38] BURRIS Ⅲ H A, OKUSAKA T, VOGEL A, et al. Patient-reported outcomes for the phase 3 topaz-1 study of durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer[J]. J Clin Oncol, 2022, 40(16 Suppl): 4070-4070.
[39] GAIRING S J, THOL F, M?LLER L, et al. The addition of transarterial chemoembolization to palliative chemotherapy extends survival in intrahepatic cholangiocarcinoma[J]. J Clin Med, 2021, 10(12): 2732.
[40] KONSTANTINIDIS I T, GROOT KOERKAMP B, DO R K G, et al. Unresectable intrahepatic cholangiocarcinoma: systemic plus hepatic arterial infusion chemotherapy is associated with longer survival in comparison with systemic chemotherapy alone[J]. Cancer, 2016, 122(5): 758-765.
[41] 郑致远,颜志平.钇90放射性微球治疗肝脏恶性肿瘤的应用进展[J]. 复旦学报(医学版), 2020, 47(4): 622-627.
[42] SCHARTZ D A, PORTER M, SCHARTZ E, et al.Transarterial yttrium-90 radioembolization for unresectable intrahepatic cholangiocarcinoma: a systematic review and Meta-analysis[J]. J Vascul Int Radiol, 2022, 33(6): 679-686.
[43] KIM Y I, PARK J W, KIM B H, et al.Outcomes of concurrent chemoradiotherapy versus chemotherapy alone for advanced-stage unresectable intrahepatic cholangiocarcinoma[J]. Radiat Oncol (London, England), 2013, 8: 292.
[44] TAO R, KRISHNAN S, BHOSALE P R, et al.Ablative radiotherapy doses lead to a substantial prolongation of survival in patients with inoperable intrahepatic cholangiocarcinoma: a retrospective dose response analysis[J]. J Clin Oncol, 2016, 34(3): 219-226.
[45] LIU C, WU K, LI J, et al.Nanoparticle-mediated therapeutic management in cholangiocarcinoma drug targeting: current progress and future prospects[J]. Biom Pharmacother, 2023, 158: 114135.
[46] ZHANG T, CHEN J, NIU L, et al.Clinical safety and efficacy of locoregional therapy combined with adoptive transfer of allogeneic γδ t cells for advanced hepatocellular carcinoma and intrahepatic cholangiocarcinoma[J]. J Vascul Int Radiol, 2022, 33(1): 19-27.
[47] 武锬洋, 张世超, 夏勇, 等. 肝内胆管癌治疗靶点的研究进展[J]. 肝胆外科杂志, 2023, 31(1): 70-73.
[48] KATO A, SHIMIZU H, OHTSUKA M, et al. Downsizing chemotherapy for initially unresectable locally advanced biliary tract cancer patients treated with gemcitabine plus cisplatin combination therapy followed by radical surgery[J]. Ann Surg Oncol, 2015, 22 Suppl 3: S1093-1099.