肝動脈灌注化療聯合度伐利尤單抗與侖伐替尼治療肝內膽管癌伴骨轉移的臨床療效_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

冉植文 ¹ , 沈舒 ¹ , 任瑩 ¹ , 馬驥 ² , 陳燁 ³ , 趙婭琴 ³ , 陳衛霞 ⁴ , 文天夫 ¹ ,  張曉赟 ¹ , 華西醫院肝癌 MDT 團隊

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

Corresponding?author：

張曉赟, Email: zhangxiaoyun@wchscu.cn

Keywords：

肝內膽管癌; 肝動脈灌注化療; 度伐利尤單抗; 侖伐替尼

DOI：

10.7507/1007-9424.202506133

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目的總結肝動脈灌注化療（GC方案）聯合度伐利尤單抗與侖伐替尼治療肝內膽管癌伴骨轉移的療效和安全性。方法回顧性分析2025年2月四川大學華西醫院收治的1例伴骨轉移的Ⅳ期肝內膽管癌患者的病例資料，該患者接受肝動脈灌注化療（GC方案）聯合度伐利尤單抗與侖伐替尼治療，總結其療效及安全性。結果該例伴骨轉移的Ⅳ期肝內膽管癌患者經6周期肝動脈灌注化療（GC方案）聯合度伐利尤單抗與侖伐替尼治療后獲得部分緩解并成功實施根治性切除，術后病理顯示約50%的腫瘤壞死。結論初步結果顯示，肝動脈灌注化療（GC方案）聯合度伐利尤單抗與侖伐替尼在伴骨轉移的肝內膽管癌中顯示出潛在療效，可能為此類不可切除患者提供轉化治療機會。

Citation： 冉植文, 沈舒, 任瑩, 馬驥, 陳燁, 趙婭琴, 陳衛霞, 文天夫, 張曉赟, 華西醫院肝癌 MDT 團隊. 肝動脈灌注化療聯合度伐利尤單抗與侖伐替尼治療肝內膽管癌伴骨轉移的臨床療效. 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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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.
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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.
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.
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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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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. 中華人民共和國國家衛生健康委員會. 原發性肝癌診療指南 (2024年版). 腫瘤綜合治療電子雜志, 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

肝動脈灌注化療聯合度伐利尤單抗與侖伐替尼治療肝內膽管癌伴骨轉移的臨床療效

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