Research progress of conversion therapy in hepatocellular carcinoma_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

LAN Chenlu ¹ , ZENG Zhiming ² , ZHU Guangzhi ¹ ,  PENG Tao ^1,3

1. Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, P. R. China;
2. Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, P. R. China;
3. Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning 530021, P. R. China;

Corresponding author：

PENG Tao, Email: pengtaogmu@163.com

Keywords：

[Kedwords]hepatocellular carcinoma; conversion therapy; unresectable

DOI：

10.7507/1007-9424.202408148

Video：

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Primary liver cancer (hereinafter referred to as liver cancer) is the fourth most common cancer and second leading cause of cancer-related deaths of China. Hepatocellular carcinoma (HCC) accounts for 75% to 85% of liver cancers, more than half of patients with HCC present at an advanced stage where surgery is not suitable. Conversion therapy can provide the opportunity for some unresectable patients to realize surgical resection. With the progress of non-surgical treatments for liver cancer, increased emphasis on comprehensive treatment approaches, and continuous clinical research outcome, conversion therapy of liver cancer has become a common clinical pathway in treatment practice in our country. This paper summarizes the progress in research on conversion therapy for HCC, analyzing its methods, efficacy, safety, and timing of surgery, to provide insights for the clinical practice and research of conversion treatment in HCC.

1.	姚一菲, 孙可欣, 郑荣寿. 《2022全球癌症统计报告》解读: 中国与全球对比. 中国普外基础与临床杂志, 2024, 31(7): 769-780.
2.	中国抗癌协会肝癌专业委员会转化治疗协作组. 原发性肝癌转化及围手术期治疗中国专家共识(2024版). 中华消化外科杂志, 2024, 23(4): 492-513.
3.	Sun JH, Zhang YL, Nie CH, et al. Effects of liver cirrhosis on portal vein embolization prior to right hepatectomy in patients with primary liver cancer. Oncol Lett, 2018, 15(2): 1411-1416.
4.	Huang Y, Ge W, Kong Y, et al. Preoperative portal vein embolization for liver resection: An updated meta-analysis. J Cancer, 2021, 12(6): 1770-1778.
5.	Addeo P, de Mathelin P, De Marini P, et al. Sequential ⁹⁰Y liver radioembolization and portal vein embolization: an additional strategy to downstage liver tumors and to enhance liver hypertrophy before major hepatectomies. Langenbecks Arch Surg, 2023, 408(1): 339. doi: 10.1007/s00423-023-03083-0.
6.	Zeng ZM, Zhu GZ, Huang HS, et al. Conversion hepatectomy for hepatocellular carcinoma with inadequate future-remnant-liver after portal vein ligation in combination with apatinib plus camrelizimab: A single-arm prospective pilot study (PLACES). J Clin Oncol, 2021, 39(15_suppl): e16132-e16132. doi: 10.1200/JCO.2021.39.15_suppl.e16132.
7.	Linecker M, Björnsson B, Stavrou GA, et al. Risk adjustment in ALPPS is associated with a dramatic decrease in early mortality and morbidity. Ann Surg, 2017, 266(5): 779-786.
8.	Wanis KN, Linecker M, Madenci AL, et al. Variation in complications and mortality following ALPPS at early-adopting centers. HPB (Oxford), 2021, 23(1): 46-55.
9.	徐邦浩, 蓝祝晶, 朱海, 等. 联合肝实质分隔和门静脉结扎的二步肝切除术式演变进展. 中国普外基础与临床杂志, 2023, 30(7): 870-876.
10.	Yu T, Ye X, Wen Z, et al. Intraoperative indocyanine green retention test of left hemiliver in decision-making for patients with hepatocellular carcinoma undergoing right hepatectomy. Front Surg, 2021, 8: 709017. doi: 10.3389/fsurg.2021.709017.
11.	Pei Y, Li W, Wang Z, et al. Successful conversion therapy for unresectable hepatocellular carcinoma is getting closer: A systematic review and meta-analysis. Front Oncol, 2022, 12: 978823. doi: 10.3389/fonc.2022.978823.
12.	Chiu SH, Chang PY, Shih YL, et al. Efficacy and safety of supplemental transarterial chemoembolization through extrahepatic collateral arteries with drug-eluting Beads: Treatment for unresectable hepatocellular carcinoma. Drug Des Devel Ther, 2020, 14: 5029-5041.
13.	Li B, Qiu J, Zheng Y, et al. Conversion to resectability using transarterial chemoembolization combined with hepatic arterial infusion chemotherapy for initially unresectable hepatocellular carcinoma. Ann Surg Open, 2021, 2(2): e057. doi: 10.1097/AS9.0000000000000057.
14.	Yoon SM, Ryoo BY, Lee SJ, et al. Efficacy and safety of transarterial chemoembolization plus external beam radiotherapy vs sorafenib in hepatocellular carcinoma with macroscopic vascular invasion: A randomized clinical trial. JAMA Oncol, 2018, 4(5): 661-669.
15.	Lyu N, Wang X, Li JB, et al. Arterial chemotherapy of oxaliplatin plus fluorouracil versus sorafenib in advanced hepatocellular carcinoma: A biomolecular exploratory, randomized, phase Ⅲ trial (FOHAIC-1). J Clin Oncol, 2022, 40(5): 468-480.
16.	Li QJ, He MK, Chen HW, et al. Hepatic arterial infusion of oxaliplatin, fluorouracil, and leucovorin versus transarterial chemoembolization for large hepatocellular carcinoma: A randomized phase Ⅲ trial. J Clin Oncol, 2022, 40(2): 150-160.
17.	Deng M, Cai H, He B, et al. Hepatic arterial infusion chemotherapy versus transarterial chemoembolization, potential conversion therapies for single huge hepatocellular carcinoma: a retrospective comparison study. Int J Surg, 2023, 109(11): 3303-3311.
18.	Lee HS, Choi GH, Choi JS, et al. Surgical resection after down-staging of locally advanced hepatocellular carcinoma by localized concurrent chemoradiotherapy. Ann Surg Oncol, 2014, 21(11): 3646-3653.
19.	Yu CY, Huang PH, Tsang LL, et al. Yttrium-90 radioembolization as the major treatment of hepatocellular carcinoma. J Hepatocell Carcinoma, 2023, 10: 17-26.
20.	Dhondt E, Lambert B, Hermie L, et al. ⁹⁰Y radioembolization versus drug-eluting bead chemoembolization for unresectable hepatocellular carcinoma: results from the TRACE phase Ⅱ randomized controlled trial. Radiology, 2022, 303(3): 699-710.
21.	Shindoh J, Kawamura Y, Kobayashi Y, et al. Prognostic impact of surgical intervention after lenvatinib treatment for advanced hepatocellular carcinoma. Ann Surg Oncol, 2021, 28(12): 7663-7672.
22.	Tada M, Ichida A, Arita J, et al. Multicenter prospective study to evaluate the efficacy of lenvatinib to achieve conversion surgery for initially unresectable hepatocellular carcinoma: LENS-HCC trial. J Clin Oncol, 2022, 40(4_suppl): 458. doi: 10.1200/JCO.2022.40.4_suppl.458.
23.	Yi Y, Sun BY, Weng JL, et al. Lenvatinib plus anti-PD-1 therapy represents a feasible conversion resection strategy for patients with initially unresectable hepatocellular carcinoma: A retrospective study. Front Oncol, 2022, 12: 1046584. doi: 10.3389/fonc.2022.1046584.
24.	Peng Z, Fan W, Zhu B, et al. Lenvatinib combined with transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma: A phase Ⅲ, randomized clinical trial (LAUNCH). J Clin Oncol, 2023, 41(1): 117-127.
25.	Liu QQ, Wang XX, Ji H, et al. The efficacy and safety of PD-1 inhibitor combined with TACE in the first-line treatment of unresectable hepatocellular carcinoma. Med Oncol, 2024, 41(5): 91. doi: 10.1007/s12032-024-02309-5.
26.	Li W, Pei Y, Wang Z, et al. Efficacy of transarterial chemoembolization monotherapy or combination conversion therapy in unresectable hepatocellular carcinoma: A systematic review and meta-analysis. Front Oncol, 2022, 12: 930868. doi: 10.3389/fonc.2022.930868.
27.	Liu W, Xie Z, Shen K, et al. Analysis of the safety and effectiveness of TACE combined with targeted immunotherapy in the treatment of intermediate and advanced hepatocellular carcinoma. Med Oncol, 2023, 40(9): 251. doi: 10.1007/s12032-023-02082-x.
28.	Wu JY, Yin ZY, Bai YN, et al. Lenvatinib combined with anti-PD-1 antibodies plus transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma: A multicenter retrospective study. J Hepatocell Carcinoma, 2021, 8: 1233-1240.
29.	Zhang XY, Liu C, Lu WS, et al. The safety and efficacy of lenvatinib combined with TACE and PD-1 inhibitors (Len-TAP) versus TACE alone in the conversion resection for initially unresectable hepatocellular carcinoma: Interim results from a multicenter prospective cohort study. Annual Meeting of the European-Society-for-Medical-Oncology(ESMO). Ann Oncol, 2022, 33(7): S870. doi: 10.1016/j.annonc.2022.07.839.
30.	Jin ZC, Chen JJ, Zhu XL, et al. Immune checkpoint inhibitors and anti-vascular endothelial growth factor antibody/tyrosine kinase inhibitors with or without transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma (CHANCE2201): a target trial emulation study. EClinicalMedicine, 2024, 72: 102622. doi: 10.1016/j.eclinm.2024.102622.
31.	He M, Li Q, Zou R, et al. Sorafenib plus hepatic arterial infusion of oxaliplatin, fluorouracil, and leucovorin vs sorafenib alone for hepatocellular carcinoma with portal vein invasion: A randomized clinical trial. JAMA Oncol, 2019, 5(7): 953-960.
32.	Xu L, Zhang YJ, Chen, MS, et al. Hepatic arterial infusion chemotherapy in combination with PD-1 inhibitor as conversion therapy in locally advanced, potentially resectable hepatocellular carcinoma: A phaseⅡ study. J Hepatol, 2021, 75: S247.
33.	Zhu XD, Huang C, Shen YH, et al. Downstaging and resection of initially unresectable hepatocellular carcinoma with tyrosine kinase inhibitor and anti-PD-1 antibody combinations. Liver Cancer, 2021, 10(4): 320-329.
34.	Zhang W, Zhang K, Liu C, et al. Hepatic arterial infusion chemotherapy combined with anti-PD-1/PD-L1 immunotherapy and molecularly targeted agents for advanced hepatocellular carcinoma: A real world study. Front Immunol, 2023, 14: 1127349. doi: 10.3389/fimmu.2023.1127349.
35.	Chang X, Wu H, Ning S, et al. Hepatic arterial infusion chemotherapy combined with lenvatinib plus humanized programmed death receptor-1 in patients with high-risk advanced hepatocellular carcinoma: A real-world study. J Hepatocell Carcinoma, 2023, 10: 1497-1509.
36.	Liu D, Mu H, Liu C, et al. Sintilimab, bevacizumab biosimilar, and HAIC for unresectable hepatocellular carcinoma conversion therapy: a prospective, single-arm phaseⅡtrial. Neoplasma, 2023, 70(6): 811-818.
37.	Chiang CL, Lee FAS, Chan KSK, et al. Survival outcome analysis of stereotactic body radiotherapy and immunotherapy (SBRT-IO) versus SBRT-alone in unresectable hepatocellular carcinoma. Liver Cancer, 2023, 13(3): 265-276.
38.	de la Torre-Aláez M, Matilla A, Varela M, et al. Nivolumab after selective internal radiation therapy for the treatment of hepatocellular carcinoma: A phase 2, single-arm study. J Immunother Cancer, 2022, 10(11): e005457. doi: 10.1136/jitc-2022-005457.
39.	Hu Y, Zhou M, Tang J, et al. Efficacy and safety of stereotactic body radiotherapy combined with camrelizumab and apatinib in patients with hepatocellular carcinoma with portal vein tumor thrombus. Clin Cancer Res, 2023, 29(20): 4088-4097.
40.	Zhang Y, Huang G, Wang Y, et al. Is salvage liver resection necessary for initially unresectable hepatocellular carcinoma patients downstaged by transarterial chemoembolization? Ten years of experience. Oncologist, 2016, 21(12): 1442-1449.
41.	Li B, Wang C, He W, et al. Watch-and-wait strategy vs. resection in patients with radiologic complete response after conversion therapy for initially unresectable hepatocellular carcinoma: a propensity score-matching comparative study. Int J Surg, 2024, 110(5): 2545-2555.

1. 姚一菲, 孙可欣, 郑荣寿. 《2022全球癌症统计报告》解读: 中国与全球对比. 中国普外基础与临床杂志, 2024, 31(7): 769-780.
2. 中国抗癌协会肝癌专业委员会转化治疗协作组. 原发性肝癌转化及围手术期治疗中国专家共识(2024版). 中华消化外科杂志, 2024, 23(4): 492-513.
3. Sun JH, Zhang YL, Nie CH, et al. Effects of liver cirrhosis on portal vein embolization prior to right hepatectomy in patients with primary liver cancer. Oncol Lett, 2018, 15(2): 1411-1416.
4. Huang Y, Ge W, Kong Y, et al. Preoperative portal vein embolization for liver resection: An updated meta-analysis. J Cancer, 2021, 12(6): 1770-1778.
5. Addeo P, de Mathelin P, De Marini P, et al. Sequential ⁹⁰Y liver radioembolization and portal vein embolization: an additional strategy to downstage liver tumors and to enhance liver hypertrophy before major hepatectomies. Langenbecks Arch Surg, 2023, 408(1): 339. doi: 10.1007/s00423-023-03083-0.
6. Zeng ZM, Zhu GZ, Huang HS, et al. Conversion hepatectomy for hepatocellular carcinoma with inadequate future-remnant-liver after portal vein ligation in combination with apatinib plus camrelizimab: A single-arm prospective pilot study (PLACES). J Clin Oncol, 2021, 39(15_suppl): e16132-e16132. doi: 10.1200/JCO.2021.39.15_suppl.e16132.
7. Linecker M, Björnsson B, Stavrou GA, et al. Risk adjustment in ALPPS is associated with a dramatic decrease in early mortality and morbidity. Ann Surg, 2017, 266(5): 779-786.
8. Wanis KN, Linecker M, Madenci AL, et al. Variation in complications and mortality following ALPPS at early-adopting centers. HPB (Oxford), 2021, 23(1): 46-55.
9. 徐邦浩, 蓝祝晶, 朱海, 等. 联合肝实质分隔和门静脉结扎的二步肝切除术式演变进展. 中国普外基础与临床杂志, 2023, 30(7): 870-876.
10. Yu T, Ye X, Wen Z, et al. Intraoperative indocyanine green retention test of left hemiliver in decision-making for patients with hepatocellular carcinoma undergoing right hepatectomy. Front Surg, 2021, 8: 709017. doi: 10.3389/fsurg.2021.709017.
11. Pei Y, Li W, Wang Z, et al. Successful conversion therapy for unresectable hepatocellular carcinoma is getting closer: A systematic review and meta-analysis. Front Oncol, 2022, 12: 978823. doi: 10.3389/fonc.2022.978823.
12. Chiu SH, Chang PY, Shih YL, et al. Efficacy and safety of supplemental transarterial chemoembolization through extrahepatic collateral arteries with drug-eluting Beads: Treatment for unresectable hepatocellular carcinoma. Drug Des Devel Ther, 2020, 14: 5029-5041.
13. Li B, Qiu J, Zheng Y, et al. Conversion to resectability using transarterial chemoembolization combined with hepatic arterial infusion chemotherapy for initially unresectable hepatocellular carcinoma. Ann Surg Open, 2021, 2(2): e057. doi: 10.1097/AS9.0000000000000057.
14. Yoon SM, Ryoo BY, Lee SJ, et al. Efficacy and safety of transarterial chemoembolization plus external beam radiotherapy vs sorafenib in hepatocellular carcinoma with macroscopic vascular invasion: A randomized clinical trial. JAMA Oncol, 2018, 4(5): 661-669.
15. Lyu N, Wang X, Li JB, et al. Arterial chemotherapy of oxaliplatin plus fluorouracil versus sorafenib in advanced hepatocellular carcinoma: A biomolecular exploratory, randomized, phase Ⅲ trial (FOHAIC-1). J Clin Oncol, 2022, 40(5): 468-480.
16. Li QJ, He MK, Chen HW, et al. Hepatic arterial infusion of oxaliplatin, fluorouracil, and leucovorin versus transarterial chemoembolization for large hepatocellular carcinoma: A randomized phase Ⅲ trial. J Clin Oncol, 2022, 40(2): 150-160.
17. Deng M, Cai H, He B, et al. Hepatic arterial infusion chemotherapy versus transarterial chemoembolization, potential conversion therapies for single huge hepatocellular carcinoma: a retrospective comparison study. Int J Surg, 2023, 109(11): 3303-3311.
18. Lee HS, Choi GH, Choi JS, et al. Surgical resection after down-staging of locally advanced hepatocellular carcinoma by localized concurrent chemoradiotherapy. Ann Surg Oncol, 2014, 21(11): 3646-3653.
19. Yu CY, Huang PH, Tsang LL, et al. Yttrium-90 radioembolization as the major treatment of hepatocellular carcinoma. J Hepatocell Carcinoma, 2023, 10: 17-26.
20. Dhondt E, Lambert B, Hermie L, et al. ⁹⁰Y radioembolization versus drug-eluting bead chemoembolization for unresectable hepatocellular carcinoma: results from the TRACE phase Ⅱ randomized controlled trial. Radiology, 2022, 303(3): 699-710.
21. Shindoh J, Kawamura Y, Kobayashi Y, et al. Prognostic impact of surgical intervention after lenvatinib treatment for advanced hepatocellular carcinoma. Ann Surg Oncol, 2021, 28(12): 7663-7672.
22. Tada M, Ichida A, Arita J, et al. Multicenter prospective study to evaluate the efficacy of lenvatinib to achieve conversion surgery for initially unresectable hepatocellular carcinoma: LENS-HCC trial. J Clin Oncol, 2022, 40(4_suppl): 458. doi: 10.1200/JCO.2022.40.4_suppl.458.
23. Yi Y, Sun BY, Weng JL, et al. Lenvatinib plus anti-PD-1 therapy represents a feasible conversion resection strategy for patients with initially unresectable hepatocellular carcinoma: A retrospective study. Front Oncol, 2022, 12: 1046584. doi: 10.3389/fonc.2022.1046584.
24. Peng Z, Fan W, Zhu B, et al. Lenvatinib combined with transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma: A phase Ⅲ, randomized clinical trial (LAUNCH). J Clin Oncol, 2023, 41(1): 117-127.
25. Liu QQ, Wang XX, Ji H, et al. The efficacy and safety of PD-1 inhibitor combined with TACE in the first-line treatment of unresectable hepatocellular carcinoma. Med Oncol, 2024, 41(5): 91. doi: 10.1007/s12032-024-02309-5.
26. Li W, Pei Y, Wang Z, et al. Efficacy of transarterial chemoembolization monotherapy or combination conversion therapy in unresectable hepatocellular carcinoma: A systematic review and meta-analysis. Front Oncol, 2022, 12: 930868. doi: 10.3389/fonc.2022.930868.
27. Liu W, Xie Z, Shen K, et al. Analysis of the safety and effectiveness of TACE combined with targeted immunotherapy in the treatment of intermediate and advanced hepatocellular carcinoma. Med Oncol, 2023, 40(9): 251. doi: 10.1007/s12032-023-02082-x.
28. Wu JY, Yin ZY, Bai YN, et al. Lenvatinib combined with anti-PD-1 antibodies plus transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma: A multicenter retrospective study. J Hepatocell Carcinoma, 2021, 8: 1233-1240.
29. Zhang XY, Liu C, Lu WS, et al. The safety and efficacy of lenvatinib combined with TACE and PD-1 inhibitors (Len-TAP) versus TACE alone in the conversion resection for initially unresectable hepatocellular carcinoma: Interim results from a multicenter prospective cohort study. Annual Meeting of the European-Society-for-Medical-Oncology(ESMO). Ann Oncol, 2022, 33(7): S870. doi: 10.1016/j.annonc.2022.07.839.
30. Jin ZC, Chen JJ, Zhu XL, et al. Immune checkpoint inhibitors and anti-vascular endothelial growth factor antibody/tyrosine kinase inhibitors with or without transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma (CHANCE2201): a target trial emulation study. EClinicalMedicine, 2024, 72: 102622. doi: 10.1016/j.eclinm.2024.102622.
31. He M, Li Q, Zou R, et al. Sorafenib plus hepatic arterial infusion of oxaliplatin, fluorouracil, and leucovorin vs sorafenib alone for hepatocellular carcinoma with portal vein invasion: A randomized clinical trial. JAMA Oncol, 2019, 5(7): 953-960.
32. Xu L, Zhang YJ, Chen, MS, et al. Hepatic arterial infusion chemotherapy in combination with PD-1 inhibitor as conversion therapy in locally advanced, potentially resectable hepatocellular carcinoma: A phaseⅡ study. J Hepatol, 2021, 75: S247.
33. Zhu XD, Huang C, Shen YH, et al. Downstaging and resection of initially unresectable hepatocellular carcinoma with tyrosine kinase inhibitor and anti-PD-1 antibody combinations. Liver Cancer, 2021, 10(4): 320-329.
34. Zhang W, Zhang K, Liu C, et al. Hepatic arterial infusion chemotherapy combined with anti-PD-1/PD-L1 immunotherapy and molecularly targeted agents for advanced hepatocellular carcinoma: A real world study. Front Immunol, 2023, 14: 1127349. doi: 10.3389/fimmu.2023.1127349.
35. Chang X, Wu H, Ning S, et al. Hepatic arterial infusion chemotherapy combined with lenvatinib plus humanized programmed death receptor-1 in patients with high-risk advanced hepatocellular carcinoma: A real-world study. J Hepatocell Carcinoma, 2023, 10: 1497-1509.
36. Liu D, Mu H, Liu C, et al. Sintilimab, bevacizumab biosimilar, and HAIC for unresectable hepatocellular carcinoma conversion therapy: a prospective, single-arm phaseⅡtrial. Neoplasma, 2023, 70(6): 811-818.
37. Chiang CL, Lee FAS, Chan KSK, et al. Survival outcome analysis of stereotactic body radiotherapy and immunotherapy (SBRT-IO) versus SBRT-alone in unresectable hepatocellular carcinoma. Liver Cancer, 2023, 13(3): 265-276.
38. de la Torre-Aláez M, Matilla A, Varela M, et al. Nivolumab after selective internal radiation therapy for the treatment of hepatocellular carcinoma: A phase 2, single-arm study. J Immunother Cancer, 2022, 10(11): e005457. doi: 10.1136/jitc-2022-005457.
39. Hu Y, Zhou M, Tang J, et al. Efficacy and safety of stereotactic body radiotherapy combined with camrelizumab and apatinib in patients with hepatocellular carcinoma with portal vein tumor thrombus. Clin Cancer Res, 2023, 29(20): 4088-4097.
40. Zhang Y, Huang G, Wang Y, et al. Is salvage liver resection necessary for initially unresectable hepatocellular carcinoma patients downstaged by transarterial chemoembolization? Ten years of experience. Oncologist, 2016, 21(12): 1442-1449.
41. Li B, Wang C, He W, et al. Watch-and-wait strategy vs. resection in patients with radiologic complete response after conversion therapy for initially unresectable hepatocellular carcinoma: a propensity score-matching comparative study. Int J Surg, 2024, 110(5): 2545-2555.

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