肝动脉灌注化疗联合度伐利尤单抗与仑伐替尼治疗肝内胆管癌伴骨转移的临床疗效_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

冉植文 ¹ , 沈舒 ¹ , 任莹 ¹ , 马骥 ² , 陈烨 ³ , 赵娅琴 ³ , 陈卫霞 ⁴ , 文天夫 ¹ ,  张晓赟 ¹ , 华西医院肝癌 MDT 团队

1. ;
2. ;
3. ;
4. ;

Corresponding author：

张晓赟, Email: zhangxiaoyun@wchscu.cn

Keywords：

肝内胆管癌; 肝动脉灌注化疗; 度伐利尤单抗; 仑伐替尼

DOI：

10.7507/1007-9424.202506133

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目的总结肝动脉灌注化疗（GC方案）联合度伐利尤单抗与仑伐替尼治疗肝内胆管癌伴骨转移的疗效和安全性。方法回顾性分析2025年2月四川大学华西医院收治的1例伴骨转移的Ⅳ期肝内胆管癌患者的病例资料，该患者接受肝动脉灌注化疗（GC方案）联合度伐利尤单抗与仑伐替尼治疗，总结其疗效及安全性。结果该例伴骨转移的Ⅳ期肝内胆管癌患者经6周期肝动脉灌注化疗（GC方案）联合度伐利尤单抗与仑伐替尼治疗后获得部分缓解并成功实施根治性切除，术后病理显示约50%的肿瘤坏死。结论初步结果显示，肝动脉灌注化疗（GC方案）联合度伐利尤单抗与仑伐替尼在伴骨转移的肝内胆管癌中显示出潜在疗效，可能为此类不可切除患者提供转化治疗机会。

Citation： 冉植文, 沈舒, 任莹, 马骥, 陈烨, 赵娅琴, 陈卫霞, 文天夫, 张晓赟, 华西医院肝癌 MDT 团队. 肝动脉灌注化疗联合度伐利尤单抗与仑伐替尼治疗肝内胆管癌伴骨转移的临床疗效. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2025, 32(10): 1291-1295. doi: 10.7507/1007-9424.202506133 Copy

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6.	Banales JM, Marin JJG, Lamarca A, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol, 2020, 17(9): 557-588.
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14.	Huang Y, Du Z, Kan A, et al. Clinical and biomarker analyses of hepatic arterial infusion chemotherapy plus lenvatinib and PD-1 inhibitor for patients with advanced intrahepatic cholangiocarcinoma. Front Immunol, 2024, 15: 1260191. doi: 10.3389/fimmu.2024.1260191.
15.	Zhao R, Zhou J, Miao Z, et al. Efficacy and safety of lenvatinib plus durvalumab combined with hepatic arterial infusion chemotherapy for unresectable intrahepatic cholangiocarcinoma. Front Immunol, 2024, 15: 1397827. doi: 10.3389/fimmu.2024.1397827.
16.	Kim JH, Won HJ, Shin YM, et al. Radiofrequency ablation for the treatment of primary intrahepatic cholangiocarcinoma. AJR Am J Roentgenol, 2011, 196(2): W205-W209.
17.	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. Cancer, 2011, 117(7): 1498-1505.
18.	Hyder O, Marsh JW, Salem R, et al. Intra-arterial therapy for advanced intrahepatic cholangiocarcinoma: a multi-institutional analysis. Ann Surg Oncol, 2013, 20(12): 3779-3786.
19.	Ibrahim SM, Mulcahy MF, Lewandowski RJ, et al. Treatment of unresectable cholangiocarcinoma using yttrium-90 microspheres: results from a pilot study. Cancer, 2008, 113(8): 2119-2128.
20.	Saxena A, Bester L, Chua TC, et al. Yttrium-90 radiotherapy for unresectable intrahepatic cholangiocarcinoma: a preliminary assessment of this novel treatment option. Ann Surg Oncol, 2010, 17(2): 484-491.
21.	Kim GH, Kim PH, Kim JH, et al. Thermal ablation in the treatment of intrahepatic cholangiocarcinoma: a systematic review and meta-analysis. Eur Radiol, 2022, 32(2): 1205-1215.
22.	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. Eur J Gastroenterol Hepatol, 2012, 24(4): 437-443.
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24.	Robinson TJ, Du L, Matsuoka L, et al. Survival and toxicities after yttrium-90 transarterial radioembolization of cholangiocarcinoma in the RESiN Registry. J Vasc Interv Radiol, 2023, 34(4): 694-701.
25.	Mambrini A, Guglielmi A, Pacetti P, et al. Capecitabine plus hepatic intra-arterial epirubicin and cisplatin in unresectable biliary cancer: a phase Ⅱ study. Anticancer Res, 2007, 27(4C): 3009-3013.
26.	Boehm LM, Jayakrishnan TT, Miura JT, et al. Comparative effectiveness of hepatic artery based therapies for unresectable intrahepatic cholangiocarcinoma. J Surg Oncol, 2015, 111(2): 213-220.
27.	Konstantinidis IT, Groot Koerkamp B, Do RK, et al. Unresectable intrahepatic cholangiocarcinoma: systemic plus hepatic arterial infusion chemotherapy is associated with longer survival in comparison with systemic chemotherapy alone. Cancer, 2016, 122(5): 758-765.
28.	Konstantinidis IT, Do RK, Gultekin DH, et al. Regional chemotherapy for unresectable intrahepatic cholangiocarcinoma: a potential role for dynamic magnetic resonance imaging as an imaging biomarker and a survival update from two prospective clinical trials. Ann Surg Oncol, 2014, 21(8): 2675-2683.
29.	Yang Z, Fu Y, Wu W, et al. Comparison of hepatic arterial infusion chemotherapy with mFOLFOX vs. first-line systemic chemotherapy in patients with unresectable intrahepatic cholangiocarcinoma. Front Pharmacol, 2023, 14: 1234342. doi: 10.3389/fphar.2023.1234342.
30.	Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science, 2005, 307(5706): 58-62.
31.	Noman MZ, Hasmim M, Lequeux A, et al. Improving cancer immunotherapy by targeting the hypoxic tumor microenvironment: new opportunities and challenges. Cells, 2019, 8(9): 1083. doi: 10.3390/cells8091083.
32.	Kato Y, Tabata K, Kimura T, et al. Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8⁺ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway. PLoS One, 2019, 14(2): e0212513. doi: 10.1371/journal.pone.0212513.
33.	Villanueva L, Lwin Z, Chung HCC, et al. Lenvatinib plus pembrolizumab for patients with previously treated biliary tract cancers in the multicohort phase 2 LEAP-005 study. J Clin Oncol, 2021, 39(15_suppl): 4080. doi: 10.1200/JCO.2021.39.15_suppl.4080.
34.	Finn RS, Ikeda M, Zhu AX, et al. Phase Ⅰb study of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma. J Clin Oncol, 2020, 38(26): 2960-2970.
35.	Fukumura D, Kloepper J, Amoozgar Z, et al. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol, 2018, 15(5): 325-340.

1. Valle JW, Kelley RK, Nervi B, et al. Biliary tract cancer. Lancet, 2021, 397(10272): 428-444.
2. Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2022. CA Cancer J Clin, 2022, 72(1): 7-33.
3. Beal EW, Tumin D, Moris D, et al. Cohort contributions to trends in the incidence and mortality of intrahepatic cholangiocarcinoma. Hepatobiliary Surg Nutr, 2018, 7(4): 270-276.
4. Saha SK, Zhu AX, Fuchs CS, et al. Forty-year trends in cholangiocarcinoma incidence in the U. S. : intrahepatic disease on the rise. Oncologist, 2016, 21(5): 594-599.
5. Han B, Zheng R, Zeng H, et al. Cancer incidence and mortality in China, 2022. J Natl Cancer Cent, 2024, 4(1): 47-53.
6. Banales JM, Marin JJG, Lamarca A, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol, 2020, 17(9): 557-588.
7. Park J, Kim MH, Kim KP, et al. Natural history and prognostic factors of advanced cholangiocarcinoma without surgery, chemotherapy, or radiotherapy: a large-scale observational study. Gut Liver, 2009, 3(4): 298-305.
8. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med, 2010, 362(14): 1273-1281.
9. Oh DY, Ruth He A, Qin S, et al. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer. NEJM Evid, 2022, 1(8): EVIDoa2200015. doi: 10.1056/EVIDoa2200015.
10. Kelley RK, 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. Lancet, 2023, 401(10391): 1853-1865.
11. 中华人民共和国国家卫生健康委员会. 原发性肝癌诊疗指南 (2024年版). 肿瘤综合治疗电子杂志, 2024, 10(3): 17-68.
12. Wang X, Fu S, Zheng K, et al. A phase Ⅱ trial of hepatic arterial infusion chemotherapy and bevacizumab in combination with toripalimab for advanced biliary tract cancers: interim report. Ann Oncol, 2022, 33(7): S568. doi: 10.1016/j.annonc.2022.07.088.
13. Wei Z, Wang Y, Wu B, et al. Hepatic arterial infusion chemotherapy plus lenvatinib with or without programmed cell death protein-1 inhibitors for advanced cholangiocarcinoma. Front Immunol, 2023, 14: 1235724. doi: 10.3389/fimmu.2023.1235724.
14. Huang Y, Du Z, Kan A, et al. Clinical and biomarker analyses of hepatic arterial infusion chemotherapy plus lenvatinib and PD-1 inhibitor for patients with advanced intrahepatic cholangiocarcinoma. Front Immunol, 2024, 15: 1260191. doi: 10.3389/fimmu.2024.1260191.
15. Zhao R, Zhou J, Miao Z, et al. Efficacy and safety of lenvatinib plus durvalumab combined with hepatic arterial infusion chemotherapy for unresectable intrahepatic cholangiocarcinoma. Front Immunol, 2024, 15: 1397827. doi: 10.3389/fimmu.2024.1397827.
16. Kim JH, Won HJ, Shin YM, et al. Radiofrequency ablation for the treatment of primary intrahepatic cholangiocarcinoma. AJR Am J Roentgenol, 2011, 196(2): W205-W209.
17. 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. Cancer, 2011, 117(7): 1498-1505.
18. Hyder O, Marsh JW, Salem R, et al. Intra-arterial therapy for advanced intrahepatic cholangiocarcinoma: a multi-institutional analysis. Ann Surg Oncol, 2013, 20(12): 3779-3786.
19. Ibrahim SM, Mulcahy MF, Lewandowski RJ, et al. Treatment of unresectable cholangiocarcinoma using yttrium-90 microspheres: results from a pilot study. Cancer, 2008, 113(8): 2119-2128.
20. Saxena A, Bester L, Chua TC, et al. Yttrium-90 radiotherapy for unresectable intrahepatic cholangiocarcinoma: a preliminary assessment of this novel treatment option. Ann Surg Oncol, 2010, 17(2): 484-491.
21. Kim GH, Kim PH, Kim JH, et al. Thermal ablation in the treatment of intrahepatic cholangiocarcinoma: a systematic review and meta-analysis. Eur Radiol, 2022, 32(2): 1205-1215.
22. 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. Eur J Gastroenterol Hepatol, 2012, 24(4): 437-443.
23. Al-Adra DP, Gill RS, Axford SJ, et al. Treatment of unresectable intrahepatic cholangiocarcinoma with yttrium-90 radioembolization: a systematic review and pooled analysis. Eur J Surg Oncol, 2015, 41(1): 120-127.
24. Robinson TJ, Du L, Matsuoka L, et al. Survival and toxicities after yttrium-90 transarterial radioembolization of cholangiocarcinoma in the RESiN Registry. J Vasc Interv Radiol, 2023, 34(4): 694-701.
25. Mambrini A, Guglielmi A, Pacetti P, et al. Capecitabine plus hepatic intra-arterial epirubicin and cisplatin in unresectable biliary cancer: a phase Ⅱ study. Anticancer Res, 2007, 27(4C): 3009-3013.
26. Boehm LM, Jayakrishnan TT, Miura JT, et al. Comparative effectiveness of hepatic artery based therapies for unresectable intrahepatic cholangiocarcinoma. J Surg Oncol, 2015, 111(2): 213-220.
27. Konstantinidis IT, Groot Koerkamp B, Do RK, et al. Unresectable intrahepatic cholangiocarcinoma: systemic plus hepatic arterial infusion chemotherapy is associated with longer survival in comparison with systemic chemotherapy alone. Cancer, 2016, 122(5): 758-765.
28. Konstantinidis IT, Do RK, Gultekin DH, et al. Regional chemotherapy for unresectable intrahepatic cholangiocarcinoma: a potential role for dynamic magnetic resonance imaging as an imaging biomarker and a survival update from two prospective clinical trials. Ann Surg Oncol, 2014, 21(8): 2675-2683.
29. Yang Z, Fu Y, Wu W, et al. Comparison of hepatic arterial infusion chemotherapy with mFOLFOX vs. first-line systemic chemotherapy in patients with unresectable intrahepatic cholangiocarcinoma. Front Pharmacol, 2023, 14: 1234342. doi: 10.3389/fphar.2023.1234342.
30. Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science, 2005, 307(5706): 58-62.
31. Noman MZ, Hasmim M, Lequeux A, et al. Improving cancer immunotherapy by targeting the hypoxic tumor microenvironment: new opportunities and challenges. Cells, 2019, 8(9): 1083. doi: 10.3390/cells8091083.
32. Kato Y, Tabata K, Kimura T, et al. Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8⁺ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway. PLoS One, 2019, 14(2): e0212513. doi: 10.1371/journal.pone.0212513.
33. Villanueva L, Lwin Z, Chung HCC, et al. Lenvatinib plus pembrolizumab for patients with previously treated biliary tract cancers in the multicohort phase 2 LEAP-005 study. J Clin Oncol, 2021, 39(15_suppl): 4080. doi: 10.1200/JCO.2021.39.15_suppl.4080.
34. Finn RS, Ikeda M, Zhu AX, et al. Phase Ⅰb study of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma. J Clin Oncol, 2020, 38(26): 2960-2970.
35. Fukumura D, Kloepper J, Amoozgar Z, et al. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol, 2018, 15(5): 325-340.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

肝动脉灌注化疗联合度伐利尤单抗与仑伐替尼治疗肝内胆管癌伴骨转移的临床疗效

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