Efficacy and safety of transcatheter arterial chemoembolization in combination with lenvatinib in treatment of intermediate and advanced primary liver cancer：a meta<b>-</b>analysis_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

WANG Baojiang ,  CONG Peng

Division of Hepatobiliary Surgery, Nanchong Central Hospital, Second Clinical Medical College of North Sichuan Medical, Nanchong, Sichuan 637000, P. R. China;

Corresponding?author：

CONG Peng, Email: 157095916@qq.com

Keywords：

primary liver cancer; transcatheter arterial chemoembolization; lenvatinib; meta-analysis

DOI：

10.7507/1007-9424.202308015

Video：

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Objective To evaluate systematically the effectiveness and safety of transcatheter arterial chemoembolization (TACE) in combination with lenvatinib (LEN) in the treatment of intermediate and advanced primary liver cancer (PLC). Methods The relevant literature was comprehensively searched in the CNKI, VIP, Ovid, Schopus, PubMed, and other databases from the establishment of the databases to March 14, 2023. The literature was obtained according to the search strategy and the inclusion and exclusion criteria, and the data were extracted and the literature quality was evaluated. The Revman 5.4 software and Stata 15.1 software were used to conduct the meta-analysis to evaluate the effect of TACE+LEN regimen on the objective response rate (ORR), disease control rate (DCR), overall survival (OS), as well as secondary outcome indicators such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), alpha fetoprotein (AFP), and hypertension, diarrhea, hand-foot disease, fatigue, proteinuria, and fever for the patients with PLC. Results A total of 15 relevant literature was included, including 1 219 patients with PLC, 591 of whom treated with TACE+LEN and 628 treated with TACE alone. The meta-analysis results showed that the TACE+LEN regimen could increase ORR and DCR and prolong OS (P<0.01), as well as effectively decrease AFP level (P<0.01). However, TACE+LEN regimen increased the risks of hypertension, diarrhea, hand-foot disease, fatigue, and proteinuria as compared with TACE alone treatment (P<0.05). However, there were no statistical impacts on AST and ALT, or the risk of fever (P>0.05). Conclusion From the results of this meta-analysis, TACE+LEN regimen has a certain efficacy in treatment of intermediate and advanced PLC, but prevention of its related complications is paid attention to.

Citation： WANG Baojiang, CONG Peng. Efficacy and safety of transcatheter arterial chemoembolization in combination with lenvatinib in treatment of intermediate and advanced primary liver cancer：a meta-analysis. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2023, 30(12): 1444-1451. doi: 10.7507/1007-9424.202308015 Copy

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2.	Llovet JM, Kelley RK, Villanueva A, et al. Hepatocellular carcinoma. Nat Rev Dis Primers, 2021, 7(1): 6.
3.	Garg T, Shrigiriwar A, Habibollahi P, et al. Intraarterial therapies for the management of hepatocellular carcinoma. Cancers (Basel), 2022, 14(14): 3351.
4.	Zou X, Xu Q, You R, et al. Efficacy and safety of TACE combined with regorafenib plus PD-1 inhibitor in the treatment of hepatocellular carcinoma after sorafenib resistance. J Hepatocell Carcinoma, 2023, 10: 267-279.
5.	Watanabe T, Koyama N. Preclinical study for antitumor mechanism of lenvatinib and clinical studies for hepatocellular carcinoma. Nihon Yakurigaku Zasshi, 2019, 153(5): 242-248.
6.	Mei Z, Gao X, Pan C, et al. Lenvatinib enhances antitumor immunity by promoting the infiltration of TCF1⁺ CD8⁺ T cells in HCC via blocking VEGFR2. Cancer Sci, 2023, 114(4): 1284-1296.
7.	朱孟超, 張慶橋, 徐浩, 等. CalliSpheres載藥微球治療原發性肝癌并發肝膿腫4例分析. 介入放射學雜志, 2020, 29(9): 939-941.
8.	中華人民共和國國家衛生健康委員會醫政醫管局. 原發性肝癌診療指南(2022年版). 中國實用外科雜志, 2022, 42(3): 241-273.
9.	張鳳琦, 翁凌凌. 侖伐替尼聯合肝動脈化療栓塞術對中晚期肝癌患者的影響. 中外醫學研究, 2022, 20(31): 33-37.
10.	張萌, 沙金平, 高毅, 等. 侖伐替尼聯合肝癌介入化療栓塞術在中晚期肝癌患者中的應用. 中西醫結合肝病雜志, 2022, 32(3): 275-276.
11.	鐘明艷, 冷幸新, 劉波, 等. 樂伐替尼聯合TACE治療不可手術切除原發性肝癌的臨床研究. 江西醫藥, 2022, 57(1): 20-23.
12.	馮錦榮, 何沙, 陳鵬貽, 等. 經導管肝動脈化療栓塞聯合侖伐替尼治療對晚期肝癌患者腫瘤壞死體積及并發癥的影響. 中文科技期刊數據庫(引文版)醫藥衛生, 2022(12): 43-46.
13.	李冰, 馬南, 楊勝楠, 等. 侖伐替尼聯合經導管動脈栓塞化療治療老年原發性肝癌的療效. 癌癥進展, 2022, 20(11): 1121-1124.
14.	劉耀鴻, 林宜圣, 楊榮煥, 等. 侖伐替尼聯合肝動脈化療栓塞術對中晚期原發性肝癌患者近期療效、T淋巴細胞免疫功能及預后的影響. 臨床誤診誤治, 2022, 35(7): 60-63.
15.	艾寧, 楊凱, 王永中, 等. 經肝動脈灌注化療栓塞術聯合甲磺酸侖伐替尼在中晚期肝癌患者中的應用. 中華實驗外科雜志, 2022, 39(5): 938-940.
16.	王洪云. 甲磺酸侖伐替尼聯合TACE治療中晚期原發性肝癌的臨床效果及安全性分析. 中國醫學創新, 2020, 17(31): 6-9.
17.	劉娟, 廖豪杰, 袁國盛, 等. 肝動脈化療栓塞術聯合侖伐替尼治療中晚期肝細胞肝癌的臨床療效及安全性分析. 實用醫院臨床雜志, 2022, 19(1): 55-59.
18.	顏羽西, 孫沛達, 李瑩. 肝動脈化療栓塞術聯合侖伐替尼治療中晚期肝癌的臨床效果. 名醫, 2022(19): 165-167.
19.	董龍科, 江昊. 肝動脈化療栓塞聯合侖伐替尼靶向治療中晚期肝細胞癌的臨床效果. 臨床醫學研究與實踐, 2022, 7(1): 42-45.
20.	Fu Z, Li X, Zhong J, et al. Lenvatinib in combination with transarterial chemoembolization for treatment of unresectable hepatocellular carcinoma (uHCC): a retrospective controlled study. Hepatol Int, 2021, 15(3): 663-675.
21.	Xie QY, Huang LP, Gao FW, et al. Efficacy of lenvatinib combined with sequential transarterial chemoembolization for primary hepatocellular carcinoma and the effects on serum basic fibroblast growth factor and vascular endothelial growth factor. Front Pharmacol, 2022, 13: 965770.
22.	Chen YX, Zhang JX, Zhou CG, et al. Comparison of the efficacy and safety of transarterial chemoembolization with or without lenvatinib for unresectable hepatocellular carcinoma: a retrospective propensity score-matched analysis. J Hepatocell Carcinoma, 2022, 9: 685-694.
23.	黨之俊, 溫樹偉, 趙玉山, 等. CalliSpheres載藥栓塞微球聯合侖伐替尼治療原發性肝癌的效果及安全性分析. 中國臨床實用醫學, 2021, 12(2): 43-46.
24.	Villarruel-Melquiades F, Mendoza-Garrido ME, García-Cuellar CM, et al. Current and novel approaches in the pharmacological treatment of hepatocellular carcinoma. World J Gastroenterol, 2023, 29(17): 2571-2599.
25.	European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol, 2018, 69(1): 182-236.
26.	Brown ZJ, Tsilimigras DI, Ruff SM, et al. Management of hepatocellular carcinoma: a review. JAMA Surg, 2023, 158(4): 410-420.
27.	Liu R, Zhu L, Yu C, et al. Quantitative evaluation of the compatibility effects of aidi injection on the treatment of hepatocellular carcinoma using targeted metabolomics: a new strategy on the mechanism study of an anticancer compound in traditional Chinese medicine. World J Tradit Chin Med, 2021, 7(1): 111-119.
28.	Moon H, Ro SW. MAPK/ERK signaling pathway in hepatocellular carcinoma. Cancers (Basel), 2021, 13(12): 3026.
29.	Jindal A, Thadi A, Shailubhai K. Hepatocellular carcinoma: etiology and current and future drugs. J Clin Exp Hepatol, 2019, 9(2): 221-232.
30.	Fan G, Wei X, Xu X. Is the era of sorafenib over? A review of the literature. Ther Adv Med Oncol, 2020, 12: 1758835920927602. doi: 10.1177/1758835920927602.
31.	宋巖. 索拉非尼與侖伐替尼肝癌一線治療之爭. 肝癌電子雜志, 2018, 5(4): 13-15.
32.	Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet, 2018, 391(10126): 1163-1173.
33.	Chen J, Lai L, Zhou C, et al. Safety, efficacy, and survival of drug-eluting beads-transarterial chemoembolization vs. conventional-transarterial chemoembolization in advanced HCC patients with main portal vein tumor thrombus. Cancer Imaging, 2023, 23(1): 70.
34.	Shi Z, Wang D, Kang T, et al. Comparison of CalliSpheres? microspheres drug-eluting beads and conventional transarterial chemoembolization in hepatocellular carcinoma patients: a randomized controlled trial. Radiol Oncol, 2023, 57(1): 70-79.
35.	Zhou GH, Han J, Sun JH, et al. Efficacy and safety profile of drug-eluting beads transarterial chemoembolization by CalliSpheres? beads in Chinese hepatocellular carcinoma patients. BMC Cancer, 2018, 18(1): 644.
36.	Wu B, Zhou J, Ling G, et al. CalliSpheres drug-eluting beads versus lipiodol transarterial chemoembolization in the treatment of hepatocellular carcinoma: a short-term efficacy and safety study. World J Surg Oncol, 2018, 16(1): 69.
37.	He M, Jiang N, Yin X, et al. Conventional and drug-eluting beads transarterial chemoembolization in patients with unresectable intrahepatic cholangiocarcinoma: a systematic review and pooled analysis. J Cancer Res Clin Oncol, 2023, 149(1): 531-540.
38.	馬婧嶔, 楊敏捷, 顏志平. 精細TACE的治療目標與栓塞終點. 外科理論與實踐, 2022, 27(2): 131-133.
39.	Zhang W, Zhou YJ, Yan ZP. Further discussion on the precision TACE therapy. J Interv Radiol, 2021, 30: 971-975.
40.	Wang LZ, Hu XX, Shen XC, et al. Intraarterial lidocaine administration for pain control by water-in-oil technique in transarterial chemoembolization: in vivo and randomized clinical trial. J Hepatocell Carcinoma, 2021, 8: 1221-1232.
41.	Ogasawara S, Chiba T, Ooka Y, et al. A randomized placebo-controlled trial of prophylactic dexamethasone for transcatheter arterial chemoembolization. Hepatology, 2018, 67(2): 575-585.
42.	Iwamoto H, Suzuki H, Shimose S, et al. Weekends-off lenvatinib for unresectable hepatocellular carcinoma improves therapeutic response and tolerability toward adverse events. Cancers (Basel), 2020, 12(4): 1010.
43.	Okubo H, Ando H, Ishizuka K, et al. Carnitine insufficiency is associated with fatigue during lenvatinib treatment in patients with hepatocellular carcinoma. PLoS One, 2020, 15(3): e0229772.

1. Ferlay JEM, Lam F, Colombet M, et al. Global cancer observatory: cancer today. Lyon: International Agency for Research on Cancer, 2020.https://gco.iarc.fr/today (accessed Feb 27, 2021).
2. Llovet JM, Kelley RK, Villanueva A, et al. Hepatocellular carcinoma. Nat Rev Dis Primers, 2021, 7(1): 6.
3. Garg T, Shrigiriwar A, Habibollahi P, et al. Intraarterial therapies for the management of hepatocellular carcinoma. Cancers (Basel), 2022, 14(14): 3351.
4. Zou X, Xu Q, You R, et al. Efficacy and safety of TACE combined with regorafenib plus PD-1 inhibitor in the treatment of hepatocellular carcinoma after sorafenib resistance. J Hepatocell Carcinoma, 2023, 10: 267-279.
5. Watanabe T, Koyama N. Preclinical study for antitumor mechanism of lenvatinib and clinical studies for hepatocellular carcinoma. Nihon Yakurigaku Zasshi, 2019, 153(5): 242-248.
6. Mei Z, Gao X, Pan C, et al. Lenvatinib enhances antitumor immunity by promoting the infiltration of TCF1⁺ CD8⁺ T cells in HCC via blocking VEGFR2. Cancer Sci, 2023, 114(4): 1284-1296.
7. 朱孟超, 張慶橋, 徐浩, 等. CalliSpheres載藥微球治療原發性肝癌并發肝膿腫4例分析. 介入放射學雜志, 2020, 29(9): 939-941.
8. 中華人民共和國國家衛生健康委員會醫政醫管局. 原發性肝癌診療指南(2022年版). 中國實用外科雜志, 2022, 42(3): 241-273.
9. 張鳳琦, 翁凌凌. 侖伐替尼聯合肝動脈化療栓塞術對中晚期肝癌患者的影響. 中外醫學研究, 2022, 20(31): 33-37.
10. 張萌, 沙金平, 高毅, 等. 侖伐替尼聯合肝癌介入化療栓塞術在中晚期肝癌患者中的應用. 中西醫結合肝病雜志, 2022, 32(3): 275-276.
11. 鐘明艷, 冷幸新, 劉波, 等. 樂伐替尼聯合TACE治療不可手術切除原發性肝癌的臨床研究. 江西醫藥, 2022, 57(1): 20-23.
12. 馮錦榮, 何沙, 陳鵬貽, 等. 經導管肝動脈化療栓塞聯合侖伐替尼治療對晚期肝癌患者腫瘤壞死體積及并發癥的影響. 中文科技期刊數據庫(引文版)醫藥衛生, 2022(12): 43-46.
13. 李冰, 馬南, 楊勝楠, 等. 侖伐替尼聯合經導管動脈栓塞化療治療老年原發性肝癌的療效. 癌癥進展, 2022, 20(11): 1121-1124.
14. 劉耀鴻, 林宜圣, 楊榮煥, 等. 侖伐替尼聯合肝動脈化療栓塞術對中晚期原發性肝癌患者近期療效、T淋巴細胞免疫功能及預后的影響. 臨床誤診誤治, 2022, 35(7): 60-63.
15. 艾寧, 楊凱, 王永中, 等. 經肝動脈灌注化療栓塞術聯合甲磺酸侖伐替尼在中晚期肝癌患者中的應用. 中華實驗外科雜志, 2022, 39(5): 938-940.
16. 王洪云. 甲磺酸侖伐替尼聯合TACE治療中晚期原發性肝癌的臨床效果及安全性分析. 中國醫學創新, 2020, 17(31): 6-9.
17. 劉娟, 廖豪杰, 袁國盛, 等. 肝動脈化療栓塞術聯合侖伐替尼治療中晚期肝細胞肝癌的臨床療效及安全性分析. 實用醫院臨床雜志, 2022, 19(1): 55-59.
18. 顏羽西, 孫沛達, 李瑩. 肝動脈化療栓塞術聯合侖伐替尼治療中晚期肝癌的臨床效果. 名醫, 2022(19): 165-167.
19. 董龍科, 江昊. 肝動脈化療栓塞聯合侖伐替尼靶向治療中晚期肝細胞癌的臨床效果. 臨床醫學研究與實踐, 2022, 7(1): 42-45.
20. Fu Z, Li X, Zhong J, et al. Lenvatinib in combination with transarterial chemoembolization for treatment of unresectable hepatocellular carcinoma (uHCC): a retrospective controlled study. Hepatol Int, 2021, 15(3): 663-675.
21. Xie QY, Huang LP, Gao FW, et al. Efficacy of lenvatinib combined with sequential transarterial chemoembolization for primary hepatocellular carcinoma and the effects on serum basic fibroblast growth factor and vascular endothelial growth factor. Front Pharmacol, 2022, 13: 965770.
22. Chen YX, Zhang JX, Zhou CG, et al. Comparison of the efficacy and safety of transarterial chemoembolization with or without lenvatinib for unresectable hepatocellular carcinoma: a retrospective propensity score-matched analysis. J Hepatocell Carcinoma, 2022, 9: 685-694.
23. 黨之俊, 溫樹偉, 趙玉山, 等. CalliSpheres載藥栓塞微球聯合侖伐替尼治療原發性肝癌的效果及安全性分析. 中國臨床實用醫學, 2021, 12(2): 43-46.
24. Villarruel-Melquiades F, Mendoza-Garrido ME, García-Cuellar CM, et al. Current and novel approaches in the pharmacological treatment of hepatocellular carcinoma. World J Gastroenterol, 2023, 29(17): 2571-2599.
25. European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol, 2018, 69(1): 182-236.
26. Brown ZJ, Tsilimigras DI, Ruff SM, et al. Management of hepatocellular carcinoma: a review. JAMA Surg, 2023, 158(4): 410-420.
27. Liu R, Zhu L, Yu C, et al. Quantitative evaluation of the compatibility effects of aidi injection on the treatment of hepatocellular carcinoma using targeted metabolomics: a new strategy on the mechanism study of an anticancer compound in traditional Chinese medicine. World J Tradit Chin Med, 2021, 7(1): 111-119.
28. Moon H, Ro SW. MAPK/ERK signaling pathway in hepatocellular carcinoma. Cancers (Basel), 2021, 13(12): 3026.
29. Jindal A, Thadi A, Shailubhai K. Hepatocellular carcinoma: etiology and current and future drugs. J Clin Exp Hepatol, 2019, 9(2): 221-232.
30. Fan G, Wei X, Xu X. Is the era of sorafenib over? A review of the literature. Ther Adv Med Oncol, 2020, 12: 1758835920927602. doi: 10.1177/1758835920927602.
31. 宋巖. 索拉非尼與侖伐替尼肝癌一線治療之爭. 肝癌電子雜志, 2018, 5(4): 13-15.
32. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet, 2018, 391(10126): 1163-1173.
33. Chen J, Lai L, Zhou C, et al. Safety, efficacy, and survival of drug-eluting beads-transarterial chemoembolization vs. conventional-transarterial chemoembolization in advanced HCC patients with main portal vein tumor thrombus. Cancer Imaging, 2023, 23(1): 70.
34. Shi Z, Wang D, Kang T, et al. Comparison of CalliSpheres? microspheres drug-eluting beads and conventional transarterial chemoembolization in hepatocellular carcinoma patients: a randomized controlled trial. Radiol Oncol, 2023, 57(1): 70-79.
35. Zhou GH, Han J, Sun JH, et al. Efficacy and safety profile of drug-eluting beads transarterial chemoembolization by CalliSpheres? beads in Chinese hepatocellular carcinoma patients. BMC Cancer, 2018, 18(1): 644.
36. Wu B, Zhou J, Ling G, et al. CalliSpheres drug-eluting beads versus lipiodol transarterial chemoembolization in the treatment of hepatocellular carcinoma: a short-term efficacy and safety study. World J Surg Oncol, 2018, 16(1): 69.
37. He M, Jiang N, Yin X, et al. Conventional and drug-eluting beads transarterial chemoembolization in patients with unresectable intrahepatic cholangiocarcinoma: a systematic review and pooled analysis. J Cancer Res Clin Oncol, 2023, 149(1): 531-540.
38. 馬婧嶔, 楊敏捷, 顏志平. 精細TACE的治療目標與栓塞終點. 外科理論與實踐, 2022, 27(2): 131-133.
39. Zhang W, Zhou YJ, Yan ZP. Further discussion on the precision TACE therapy. J Interv Radiol, 2021, 30: 971-975.
40. Wang LZ, Hu XX, Shen XC, et al. Intraarterial lidocaine administration for pain control by water-in-oil technique in transarterial chemoembolization: in vivo and randomized clinical trial. J Hepatocell Carcinoma, 2021, 8: 1221-1232.
41. Ogasawara S, Chiba T, Ooka Y, et al. A randomized placebo-controlled trial of prophylactic dexamethasone for transcatheter arterial chemoembolization. Hepatology, 2018, 67(2): 575-585.
42. Iwamoto H, Suzuki H, Shimose S, et al. Weekends-off lenvatinib for unresectable hepatocellular carcinoma improves therapeutic response and tolerability toward adverse events. Cancers (Basel), 2020, 12(4): 1010.
43. Okubo H, Ando H, Ishizuka K, et al. Carnitine insufficiency is associated with fatigue during lenvatinib treatment in patients with hepatocellular carcinoma. PLoS One, 2020, 15(3): e0229772.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Efficacy and safety of transcatheter arterial chemoembolization in combination with lenvatinib in treatment of intermediate and advanced primary liver cancer：a meta-analysis

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