系统疗法改变肝癌外科的格局：机遇与挑战

doi:10.16139/j.1007-9610.2024.02.01

摘要/Abstract

摘要：

外科手术是肝细胞癌（HCC，简称肝癌）病人治疗的首选方案。然而，我国约七成HCC病人初诊时已属于进展期，失去了手术机会。近年来，系统治疗的快速发展为进展期HCC病人带来了新的希望。靶向和免疫（靶免）联合疗法或局部疗法与靶免治疗的联合方案显著改善进展期HCC的生存,改变了进展期HCC的治疗格局。此外，系统治疗也为HCC病人围术期治疗带来新的机遇。转化治疗、新辅助治疗以及术后辅助治疗等有助于增加手术治疗机会、降低术后转移和复发风险、延长HCC病人的总体生存期。以靶免联合治疗为基础的系统疗法已贯穿HCC外科治疗的全流程管理，彻底改变了HCC的外科治疗范式。然而，如何确定最佳组合、筛选敏感人群、解决耐药性以及降低全身不良事件等还需进一步探索。

关键词: 肝细胞癌, 系统治疗, 转化治疗, 新辅助治疗, 辅助治疗

Abstract:

Surgery is still the first choice for patients with hepatocellular carcinoma(HCC). However, about 70% of HCC patients in China are first diagnosed in the advanced stage and have lost the opportunity for surgery. Recently, the rapid development of systematic therapy has brought new hope for patients with advanced HCC. The combination of molecular targeted therapy and immunotherapy with or without local therapy significantly improves the survival of advanced HCC and alters the landscape of surgical treatment in advanced HCC. In addition, systemic therapy also brings new opportunities for perioperative treatment of HCC patients. Conversion therapy, neoadjuvant therapy, and postoperative adjuvant therapy can increase the chances of surgical treatment, reduce the risk of postoperative metastasis and recurrence, and prolong the overall survival of HCC patients. Systematic therapy based on molecular targeted therapy and immunotherapy has been applied through the whole process of HCC surgical treatment, and has completely altered the surgery paradigm of HCC. However, further research is needed to determine the optimal combination protocol, screen the sensitive populations, address drug resistance, and reduce systemic adverse events.

Key words: Hepatocellular carcinoma(HCC), Systemic therapy, Conversion therapy, Neoadjuvant therapy, Adjuvant therapy

中图分类号:

R735.7

邵卫清, 陆录, 钦伦秀. 系统疗法改变肝癌外科的格局：机遇与挑战[J]. 外科理论与实践, 2024, 29(02): 93-98.

SHAO Weiqing, LU Lu, QIN Lunxiu. Systemic therapy alters the landscape of surgery in hepatocellular carcinoma： opportunities and challenges[J]. Journal of Surgery Concepts & Practice, 2024, 29(02): 93-98.

参考文献 43

[1]	SUNG H, FERLAY J, SIEGEL R L, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3):209-249.
[2]	VILLANUEVA A. Hepatocellular carcinoma[J]. New Engl J Med, 2019, 380(15):1450-1462. doi: 10.1056/NEJMra1713263
[3]	SANGRO B, SAROBE P, HERVAS-STUBBS S, et al. Advances in immunotherapy for hepatocellular carcinoma[J]. Nate Rev Gastroenterol Hepatol, 2021, 18(8):525-543.
[4]	LASCHTOWITZ A, RODERBURG C, TACKE F, et al. Preoperative immunotherapy in hepatocellular carcinoma: current state of the art[J]. J Hepatocell Carcinoma, 2023,10:181-191.
[5]	XIE D Y, ZHU K, REN Z G, et al. A review of 2022 Chinese clinical guidelines on the management of hepatoce-llular carcinoma: updates and insights[J]. Hepatobiliary Surg Nutr, 2023, 12(2):216-228.
[6]	RIMASSA L, FINN R S, SANGRO B. Combination immunotherapy for hepatocellular carcinoma[J]. J Hepatol, 2023, 79(2):506-515. doi: 10.1016/j.jhep.2023.03.003 pmid: 36933770
[7]	KUDO M, FINN R S, QIN S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresec-table hepatocellular carcinoma: a randomised phase 3 non-inferiority trial[J]. Lancet, 2018, 391(10126):1163-1173.
[8]	QIN S, BI F, GU S, et al. Donafenib versus sorafenib in first-line treatment of unresectable or metastatic hepatocellular carcinoma: a randomized, open-label, parallel-controlled phase Ⅱ-Ⅲ trial[J]. J Clin Oncol, 2021, 39(27):3002-3011.
[9]	FINN R S, QIN S, IKEDA M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma[J]. N Engl J Med, 2020;382:1894-1905.
[10]	CHENG A L, QIN S, IKEDA M, et al. Updated efficacy and safety data from IMbrave150: atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma[J]. J Hepatol, 2022, 76(4):862-873.
[11]	REN Z, XU J, BAI Y, et al. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresec-table hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study[J]. Lancet Oncol, 2021, 22(7):977-990.
[12]	QIN S, CHAN S L, GU S, et al. Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresec-table hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study[J]. Lancet, 2023, 402(10408):1133-1146.
[13]	LLOVET J M, KUDO M, MERLE P, et al. Lenvatinib plus pembrolizumab versus lenvatinib plus placebo for advanced hepatocellular carcinoma (LEAP-002): a randomised, double-blind, phase 3 trial[J]. Lancet Oncol, 2023, 24(12):1399-1410.
[14]	SANGRO B, CHAN S L, KELLEY R K, et al. Four-year overall survival update from the phase Ⅲ HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma[J]. Ann Oncol, 2024, 35(5):448-457.
[15]	ZHU Y, QIN L X. Strategies for improving the efficacy of immunotherapy in hepatocellular carcinoma[J]. Hepatobiliary Pancreat Dis Int, 2022, 21(5):420-429.
[16]	中国临床肿瘤学会指南工作委员会. 中国临床肿瘤学会(CSCO):原发性肝癌诊疗指南(2022版)[M]. 北京: 人民卫生出版社, 2022.
	Chinese Clinical Oncology Society Guidelines Working Committee. Chinese Society of Clinical Oncology (CSCO):diagnosis and treatment guidelines for primary liver cancer (2022 edition)[M]. Beijing: People's Health Publishing House, 2022.
[17]	Diagnosis and Treatment Guidelines for Colorectal Cancer Working Group CSOCOC. Chinese Society of Clinical Oncology (CSCO) diagnosis and treatment guidelines for colorectal cancer 2018 (English version)[J]. Chin J Cancer Res, 2019, 31(1):117-134.
[18]	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[J]. Clin Cancer Res, 2023, 29(20):4088-4097.
[19]	CHAMSEDDINE S, LAPELUSA M, KASEB A O. Systemic neoadjuvant and adjuvant therapies in the management of hepatocellular carcinoma-a narrative review[J]. Cancers (Basel), 2023, 15(13):3508.
[20]	TANG Z Y, YU Y Q, MA Z C, et al. Conversion of surgically verified unresectable to resectable hepatoellular carcinoma - a report of 26 patients with subsequent resection[J]. Chin J Cancer Res, 1989,1:41-47.
[21]	SUN H C, ZHU X D. Downstaging conversion therapy in patients with initially unresectable advanced hepatocellular carcinoma: an overview[J]. Front Oncol, 2021,11:772195.
[22]	LAU W Y, LAI E C. Salvage surgery following downsta-ging of unresectable hepatocellular carcinoma-a strategy to increase resectability[J]. Ann Surg Oncol, 2007, 14(12):3301-3309.
[23]	WANG L J, WANG H W, CUI Y, et al. Sintilimab plus lenvatinib as conversion therapy in patients with unresectable locally intermediate to advanced hepatocellular carcinoma: a single-arm, single-center, open-label, phase 2 study[J]. J Clin Oncol, 2022, 40(4 suppl):449.
[24]	SUN H C, ZHU X D, GAO Q, et al. Sintilimab combined with bevacizumab biosimilar as a conversion therapy in potentially resectable intermediate-stage hepatocellular carcinoma (HCC): updated results of a phase Ⅱ trial[J]. J Clin Oncol, 2023, 41(16 suppl):e16220.
[25]	LIU D, MU H, LIU C, et al. Hepatic artery infusion chemotherapy (HAIC) combined with sintilimab and bevacizumab biosimilar (IBI305) for initial unresectable hepatocellular carcinoma (HCC): a prospective, single-arm phase Ⅱ trial[J]. J Clin Oncol, 2022,40:4073.
[26]	中国抗癌协会肝癌专业委员会转化治疗协作组. 肝癌转化治疗中国专家共识(2021版)[J]. 中华消化外科杂志, 2021, 20(6):600-616.
	Transformation Therapy Collaborative Group of the Liver Cancer Professional Committee of the Chinese Anti Cancer Association. Consensus of Chinese experts on liver cancer transformation therapy (2021 edition)[J]. Chin J Dig Surg, 2021, 20(6):600-616.
[27]	中国医疗保健国际交流促进会肝脏肿瘤学分会, 中国抗癌协会肝癌专业委员会, 中国医师协会肝癌专业委员会, 等. 肝细胞癌新辅助及转化治疗中国专家共识(2023版)[J]. 肝癌电子杂志, 2023, 10(4):1-14.
	Liver Oncology Branch of China International Exchange and Promotion Association for Medical and Healthcare, Liver Cancer Professional Committee of China Anti-Cancer Association, Liver Cancer Professional Committee of Chinese Medical Doctor Association, et al. Chinese expert consensus on neoadjuvant and conversion therapies for hepatocellular carcinoma (2023 Edition)[J]. Electronic J Liver Tumor, 2023, 10(4):1-14.
[28]	中华预防医学会肝胆胰疾病预防与控制专业委员会, 中国抗癌协会肝癌专业委员会, 北京医学会外科学分会肝脏学组, 等. 基于免疫联合靶向方案的晚期肝细胞癌转化治疗中国专家共识(2021版)[J]. 中华肝胆外科杂志, 2021, 27(4):241-251.
	Professional Committee for Prevention and Control of Hepatobiliary and Pancreatic Diseases of Chinese Preventive Medicine Association, Chinese Society of Liver Cancer, Liver Study Group of Surgery Committee of Beijing Medical Association, et al. Chinese expert consensus on conversion therapy of immune checkpoint inhibitors combined antiangiogenic targeted drugs for advanced hepatocellular carcinoma (2021 edition)[J]. Chin J Hepatobiliary Surg, 2021, 27(4):241-251.
[29]	LAI Z, HE M, BU X, et al. Lenvatinib, toripalimab plus hepatic arterial infusion chemotherapy in patients with high-risk advanced hepatocellular carcinoma: a biomolecular exploratory, phase Ⅱ trial[J]. Eur J Cancer, 2022,174:68-77.
[30]	CAO Y J, ZHANG X B, YUE Y, et al. Donafenib combined with camrelizumab and transarterial chemoembolization (TACE) as conversion therapy for unresectable hepatocellular carcinoma (uHCC): a prospective, single-arm, phase Ⅱ study[J]. J Clin Oncol, 2023,41:e16203.
[31]	WEN T, JIN C, FACCIORUSSO A, et al. Multidisciplinary management of recurrent and metastatic hepatocellular carcinoma after resection: an international expert consensus[J]. Hepatobiliary Surg Nutr, 2018, 7(5):353-371.
[32]	XIA Y, TANG W, QIAN X, et al. Efficacy and safety of camrelizumab plus apatinib during the perioperative period in resectable hepatocellular carcinoma: a single-arm, open label, phase Ⅱ clinical trial[J]. J Immunother Cancer, 2022, 10(4):e004656.
[33]	KASEB A O, HASANOV E, CAO H S T, et al. Perioperative nivolumab monotherapy versus nivolumab plus ipilimumab in resectable hepatocellular carcinoma: a randomised, open-label, phase 2 trial[J]. Lancet Gastroenterol Hepatol, 2022, 7(3):208-218.
[34]	WANG Z, REN Z, CHEN Y, et al. Adjuvant transarterial chemoembolization for hbv-related hepatocellular carcinoma after resection: a randomized controlled study[J]. Clin Cancer Res, 2018, 24(9):2074-2081. doi: 10.1158/1078-0432.CCR-17-2899 pmid: 29420221
[35]	LI S H, MEI J, CHENG Y, et al. Postoperative adjuvant hepatic arterial infusion chemotherapy with folfox in hepatocellular carcinoma with microvascular invasion: a multicenter, phase Ⅲ, randomized study[J]. J Clin Oncol, 2023, 41(10):1898-1908.
[36]	BRUIX J, TAKAYAMA T, MAZZAFERRO V, et al. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial[J]. Lancet Oncol, 2015, 16(13):1344-1354. doi: 10.1016/S1470-2045(15)00198-9 pmid: 26361969
[37]	CHEN J H, LU L, WEN T F, et al. Adjuvant lenvatinib in combination with TACE for hepatocellular carcinoma patients with high risk of postoperative relapse (LANCE): interim results from a muticenter prospective cohort study[J]. J Clin Oncol, 2020, 38(15 suppl):4580.
[38]	QIN S, CHEN M, CHENG A L, et al. Atezolizumab plus bevacizumab versus active surveillance in patients with resected or ablated high-risk hepatocellular carcinoma (IMbrave050): a randomised, open-label, multicentre, phase 3 trial[J]. Lancet, 2023, 402(10415):1835-1847.
[39]	KUDO M, UESHIMA K, NAKAHIRA S, et al. Final results of adjuvant nivolumab for hepatocellular carcinoma (HCC) after surgical resection (SR) or radiofrequency ablation (RFA) (NIVOLVE): a phase 2 prospective multicenter single-arm trial and exploratory biomarker analysis[J]. J Clin Oncol, 2022, 40(4 suppl):416.
[40]	WANG K, XIANG Y J, YU H M, et al. Adjuvant sinti-limab in resected high-risk hepatocellular carcinoma: a randomized, controlled, phase 2 trial[J]. Nat Med, 2024, 30(3):708-715.
[41]	ZHU A X, ABBAS A R, DE GALARRETA M R, et al. Molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma[J]. Nat Med, 2022, 28(8):1599-1611. doi: 10.1038/s41591-022-01868-2 pmid: 35739268
[42]	GRETEN T F, VILLANUEVA A, KORANGY F, et al. Biomarkers for immunotherapy of hepatocellular carcinoma[J]. Nat Rev Clin Oncol, 2023, 20(11):780-798. doi: 10.1038/s41571-023-00816-4 pmid: 37726418
[43]	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[J]. Int J Surg, 2024, 110(5):2545-2555.