经肝动脉化疗栓塞术联合卡瑞利珠单抗及阿帕替尼治疗中晚期肝细胞癌的效果及安全性分析

杨逸涵; 李婉慈; 仲斌演; 沈健; 朱晓黎

doi:10.3969/j.issn.1001-5256.2022.12.014

经肝动脉化疗栓塞术联合卡瑞利珠单抗及阿帕替尼治疗中晚期肝细胞癌的效果及安全性分析

DOI: 10.3969/j.issn.1001-5256.2022.12.014

苏州大学附属第一医院介入科，江苏苏州 215000

基金项目:

江苏省社会发展面上项目 (BE20221648)

伦理学声明：本研究于2019年6月提交苏州大学附属第一医院医学伦理委员会审查并获得批准，批号：2019伦审批135号；于中国临床试验注册中心注册，编号：ChiCTR1900027247。所有研究对象均自愿参加临床试验并签署知情同意书。

利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。

作者贡献声明：杨逸涵负责实施研究，收集与分析资料，撰写论文；朱晓黎、李婉慈参与课题设计及指导；李婉慈、仲斌演、沈健参与论文修改；朱晓黎负责指导写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
朱晓黎，zhuxiaoli90@163.com

计量
- 文章访问数: 1575
- HTML全文浏览量: 965
- PDF下载量: 85
- 被引次数: 0
出版历程
- 收稿日期: 2022-05-24
- 录用日期: 2022-07-14
- 出版日期: 2022-12-20

Efficacy and safety of transarterial chemoembolization combined with camrelizumab and apatinib in treatment of advanced hepatocellular carcinoma

Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, China

Research funding:

The Social Development General Program of Jiangsu Province (BE20221648)

More Information

Corresponding author: ZHU Xiaoli, zhuxiaoli90@163.com (ORCID: 0000-0002-3507-2018)

摘要

摘要: 目的评估经肝动脉化疗栓塞术(TACE)联合卡瑞利珠单抗及阿帕替尼治疗中晚期肝细胞癌(HCC)的疗效和安全性。方法选取2019年7月—2021年6月在苏州大学附属第一医院诊治且符合入排标准的19例中晚期HCC患者，接受TACE联合卡瑞利珠单抗及阿帕替尼治疗，依据改良实体瘤疗效评价标准(mRECIST)评估肿瘤反应，依据通用不良事件术语5.0标准(CTCAE v5.0标准)评估不良事件。采用Kaplan-Meier法对无进展生存期、总生存期进行分析并计算95%CI。结果 19例患者中位随访时间为14.0个月。截至最后一次随访，根据mRECIST标准，19例患者中有7例(36.8%)最佳反应达到完全缓解，9例(47.4%)达到部分缓解，2例(10.5%)达到疾病稳定，随访期间总客观缓解率达到84.2%，总疾病控制率达到94.7%，中位持续缓解时间达到8.0(3.4~13.0)个月，中位无进展生存期达到9.5(95% CI：4.7~14.3)个月，6个月生存率达到100%，12个月生存率达到78.9%。19例患者中发生7例(36.8%)严重不良事件。所有级别中最常见不良事件包括TACE栓塞后综合征(17例，89.5%)、肝损伤(14例，73.7%)、血液系统毒性(8例，42.1%)、蛋白尿(8例，42.1%)等。结论 TACE联合卡瑞利珠单抗及阿帕替尼治疗中晚期HCC疗效肯定，不良事件可控，为中晚期HCC患者的一线治疗提供了潜在的新治疗选择。
- 癌, 肝细胞 /
- 卡瑞利珠单抗 /
- 阿帕替尼
Abstract: Objective To investigate the efficacy and safety of transarterial chemoembolization (TACE) combined with camrelizumab and apatinib in the treatment of advanced hepatocellular carcinoma (HCC). Methods From July 2019 to June 2021, 19 patients with advanced HCC who met the inclusion and exclusion criteria in the First Affiliated Hospital of Soochow University were enrolled in this study. All patients received TACE combined with camrelizumab and apatinib. Tumor response was assessed according to Modified Response Evaluation Criteria in Solid Tumors (mRECIST), and adverse events were assessed according to Common Terminology Criteria for Adverse Events (v5.0). The Kaplan-Meier method was used to analyze progression-free survival and overall survival and calculate 95% confidence interval (CI). Results The median follow-up time was 14.0 months for the 19 patients. As of the last follow-up based on mRECIST, 7 patients (7/19, 36.8%) achieved complete response, 9 (9/19, 47.4%) achieved partial response, and 2 (2/19, 10.5%) achieved stable disease. During follow-up, overall objective response rate and overall disease control rate reached 84.2% and 94.7%, respectively; the median duration of response reached 8.0 (3.4-13.0) months, and median progression-free survival reached 9.5 (95%CI: 4.7-14.3) months; the 6-month survival rate reached 100%, and the 12-month survival rate reached 78.9%. Among the 19 patients, 7 (36.8%) experienced serious adverse events. The most common adverse events of all grades included post-embolization syndrome after TACE (17/19, 89.5%), liver injury (14/19, 73.7%), hematologic toxicity (8/19, 42.1%), and proteinuria (8/19, 42.1%). Conclusion TACE combined with camrelizumab and apatinib has marked efficacy and controllable adverse events in the treatment of advanced HCC, which provides a potential new option for the first-line treatment of advanced HCC.
- Carcinoma, Hepatocellular /
- Camrelizumab /
- Apatinib

HTML全文

图 1 TACE联合卡瑞利珠单抗及阿帕替尼治疗中晚期HCC前后影像学对比

注：患者，男性，55岁，因上腹部隐痛2周，体检发现肝占位1周入院。a，联合治疗前的腹部增强MR动脉期示，肝右叶肿瘤伴肝内多发转移(红色箭头)，腰椎及左侧肾上腺转移瘤(白色箭头)；评估为BCLC C期(CNLC Ⅲb期)；b，经过一次TACE和三个周期的卡瑞利珠单抗与阿帕替尼联合治疗后的腹部增强MR动脉期示，肝右叶肿瘤明显缩小，活性较基线时明显减低，肝内转移性病灶均缩小或消失(红色箭头)，胸椎转移瘤基本失活(白色箭头)，左侧肾上腺转移瘤消失；疗效评价为PR；c，经过满一年联合治疗后的腹部增强MR动脉期示：肝右叶肿瘤继续缩小，活性继续减低，肝内转移性病灶均失活或消失(红色箭头)，胸椎转移瘤失活(白色箭头)，左侧肾上腺转移瘤消失；疗效评价为PR；d，TACE前后腹部CT平扫对比，①肝右叶可见一低密度占位，其内密度不均(黄色箭头)，②肝右叶病灶体积较前缩小，其内碘油沉积良好(黄色箭头)。

Figure 1. Imaging comparison before and after TACE combined with camrelizumab and apatinib in the treatment of advanced HCC

下载: 全尺寸图片幻灯片

表 1 患者基线临床资料及肿瘤特征

Table 1. Baseline clinical data and tumor characteristics of the study patients

临床特征	数值
年龄(岁)	62.1±10.0
性别[例(%)]
男	16(84.2)
女	3(15.8)
ECOG评分[例(%)]
0	11(57.9)
1	8(42.1)
Child-Pugh分级[例(%)]
A	16(84.2)
B	3(15.8)
病毒性肝炎[例(%)]
乙型肝炎	18(94.7)
丙型肝炎	1(5.3)
肝硬化[例(%)]
有	16(84.2)
无	3(15.8)
BCLC分期[例(%)]
B	9(47.4)
C	10(52.6)
CNLC分期[例(%)]
Ⅱa	6(31.6)
Ⅱb	5(26.3)
Ⅲa	2(10.5)
Ⅲb	6(31.6)
门静脉癌栓[例(%)]
有	3(15.8)
无	16(84.2)
肝外转移[例(%)]
有	6(31.6)
无	13(68.4)
AFP[例(%)]
＜400 ng/mL	15(78.9)
≥400 ng/mL	4(21.1)
肿瘤大小[例(%)]
＜10 cm	16(84.2)
≥10 cm	3(15.8)
肿瘤个数[例(%)]
＜3个	8(42.1)
≥3个	11(57.9)
既往治疗[例(%)]	9(47.4)
外科手术	8(42.1)
TACE	5(26.3)
消融	1(5.3)

下载: 导出CSV

表 2 19例HCC患者TACE联合卡瑞利珠单抗及阿帕替尼治疗效果

Table 2. Effects of TACE combined with camrelizumab and apatinib in the treatment of 19 HCC patients

治疗效果	数值
最佳反应[例(%)]
CR	7(36.8)
PR	9(47.4)
SD	2(10.5)
PD	1(5.3)
ORR	16(84.2)
DCR	18(94.7)
mPFS(月)	9.5(4.7~14.3)
mDoR(月)	8.0(3.4~13.0)
6个月生存情况[例(%)]	19(100)
12个月生存情况[例(%)]	15(78.9)
注：mPFS为中位无进展生存期；mDoR为中位持续缓解时间。

下载: 导出CSV

表 3 TACE联合卡瑞利珠单抗及阿帕替尼相关不良事件

Table 3. Adverse events related to TACE combined with camrelizumab and apatinib

不良反应	1/2级	3级
TACE栓塞后综合征[例(%)]	17(89.5)	0
肝损伤[例(%)]	13(68.4)	1(5.3)
血液系统毒性[例(%)]	7(36.8)	1(5.3)
心肌损害[例(%)]	7(36.8)	0
甲状腺功能异常[例(%)]	7(36.8)	0
免疫性垂体炎[例(%)]	1(5.3)	1(5.3)
乏力[例(%)]	6(31.6)	0
高血压[例(%)]	5(26.3)	1(5.3)
蛋白尿[例(%)]	6(31.6)	2(10.5)
皮疹[例(%)]	6(31.6)	0
手足综合征[例(%)]	5(26.3)	0
脱发[例(%)]	2(10.5)	0
皮肤毛细血管增生症[例(%)]	7(36.8)	0
胃肠道反应[例(%)]	5(26.3)	0
声音嘶哑[例(%)]	5(26.3)	1(5.3)

下载: 导出CSV

参考文献(25)

[1]	SUNG H, FERLAY J, SIEGEL RL, 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. DOI: 10.3322/caac.21660.
[2]	EL-SERAG HB, RUDOLPH KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis[J]. Gastroenterology, 2007, 132(7): 2557-2576. DOI: 10.1053/j.gastro.2007.04.061.
[3]	European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma[J]. J Hepatol, 2018, 69(1): 182-236. DOI: 10.1016/j.jhep.2018.03.019.
[4]	General Office of National Health Commission. Standard for diagnosis and treatment of primary liver cancer (2022 edition)[J]. J Clin Hepatol, 2022, 38(2): 288-303. DOI: 10.3969/j.issn.1001-5256.2022.02.009. 国家卫生健康委办公厅. 原发性肝癌诊疗指南(2022年版)[J]. 临床肝胆病杂志, 2022, 38(2): 288-303. DOI: 10.3969/j.issn.1001-5256.2022.02.009.
[5]	KUDO M, MATSUI O, IZUMI N, et al. Transarterial chemoembolization failure/refractoriness: JSH-LCSGJ criteria 2014 update[J]. Oncology, 2014, 87(Suppl 1): 22-31. DOI: 10.1159/000368142.
[6]	ARIZUMI T, UESHIMA K, CHISHINA H, et al. Validation of the criteria of transcatheter arterial chemoembolization failure or refractoriness in patients with advanced hepatocellular carcinoma proposed by the LCSGJ[J]. Oncology, 2014, 87(Suppl 1): 32-36. DOI: 10.1159/000368143.
[7]	KUDO M. Systemic therapy for hepatocellular carcinoma: 2017 Update[J]. Oncology, 2017, 93(Suppl 1): 135-146. DOI: 10.1159/000481244.
[8]	KUDO M, UESHIMA K, IKEDA M, et al. Randomised, multicentre prospective trial of transarterial chemoembolisation (TACE) plus sorafenib as compared with TACE alone in patients with hepatocellular carcinoma: TACTICS trial[J]. Gut, 2020, 69(8): 1492-1501. DOI: 10.1136/gutjnl-2019-318934.
[9]	XU J, SHEN J, GU S, et al. Camrelizumab in combination with apatinib in patients with advanced hepatocellular carcinoma (RESCUE): A nonrandomized, open-label, phase Ⅱ trial[J]. Clin Cancer Res, 2021, 27(4): 1003-1011. DOI: 10.1158/1078-0432.CCR-20-2571.
[10]	REN Z, XU J, BAI Y, et al. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study[J]. Lancet Oncol, 2021, 22(7): 977-990. DOI: 10.1016/S1470-2045(21)00252-7.
[11]	FINN RS, QIN S, IKEDA M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma[J]. N Engl J Med, 2020, 382(20): 1894-1905. DOI: 10.1056/NEJMoa1915745.
[12]	QIN S, REN Z, MENG Z, et al. Camrelizumab in patients with previously treated advanced hepatocellular carcinoma: a multicentre, open-label, parallel-group, randomised, phase 2 trial[J]. Lancet Oncol, 2020, 21(4): 571-580. DOI: 10.1016/S1470-2045(20)30011-5.
[13]	QIN S, LI Q, GU S, et al. Apatinib as second-line or later therapy in patients with advanced hepatocellular carcinoma (AHELP): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial[J]. Lancet Gastroenterol Hepatol, 2021, 6(7): 559-568. DOI: 10.1016/S2468-1253(21)00109-6.
[14]	LENCIONI R, LLOVET JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma[J]. Semin Liver Dis, 2010, 30(1): 52-60. DOI: 10.1055/s-0030-1247132.
[15]	BASCH E, REEVE BB, MITCHELL SA, et al. Development of the National Cancer Institute's patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE)[J]. J Natl Cancer Inst, 2014, 106(9): 67-73. DOI: 10.1200/EDBK_159514.
[16]	JU S, ZHOU C, YANG C, et al. Apatinib plus camrelizumab with/without chemoembolization for hepatocellular carcinoma: A real-world experience of a single center[J]. Front Oncol, 2021, 11: 835889. DOI: 10.3389/fonc.2021.835889.
[17]	CAO F, YANG Y, SI T, et al. The efficacy of TACE combined with lenvatinib plus sintilimab in unresectable hepatocellular carcinoma: A multicenter retrospective study[J]. Front Oncol, 2021, 11: 783480. DOI: 10.3389/fonc.2021.783480.
[18]	LIU J, LI Z, ZHANG W, et al. Comprehensive treatment of trans-arterial chemoembolization plus lenvatinib followed by camrelizumab for advanced hepatocellular carcinoma patients[J]. Front Pharmacol, 2021, 12: 709060. DOI: 10.3389/fphar.2021.709060.
[19]	LI KY, WEI GW, LI T, et al. Diagnosis and treatment specification for immunosuppressive therapy a rejection of liver transplantation in China(2019 edition)[J]. Ogran Transplant, 2022, 13(5): 561-568. DOI: 10.3969/j.issn.1674-7445.2022.05.003. 李克跃, 魏国微, 黎涛, 等. 肝癌肝移植手术前后靶向及免疫治疗的指征及时机探讨[J]. 器官移植, 2022, 13(5): 561-568. DOI: 10.3969/j.issn.1674-7445.2022.05.003.
[20]	GOLFIERI R, RENZULLI M, MOSCONI C, et al. Hepatocellular carcinoma responding to superselective transarterial chemoembolization: an issue of nodule dimension?[J]. J Vasc Interv Radiol, 2013, 24(4): 509-517. DOI: 10.1016/j.jvir.2012.12.013.
[21]	KUDO M, HAN KH, YE SL, et al. A changing paradigm for the treatment of intermediate-stage hepatocellular carcinoma: Asia-Pacific primary liver cancer expert consensus statements[J]. Liver Cancer, 2020, 9(3): 245-260. DOI: 10.1159/000507370.
[22]	KUDO M, UESHIMA K, CHAN S, et al. Lenvatinib as an initial treatment in patients with intermediate-stage hepatocellular carcinoma beyond up-to-seven criteria and child-pugh a liver function: A proof-of-concept study[J]. Cancers (Basel), 2019, 11(8): 1084. DOI: 10.3390/cancers11081084.
[23]	SCHICHO A, HELLERBRAND C, KRVGER K, et al. Impact of different embolic agents for transarterial chemoembolization (TACE) procedures on systemic vascular endothelial growth factor (VEGF) levels[J]. J Clin Transl Hepatol, 2016, 4(4): 288-292. DOI: 10.14218/JCTH.2016.00058.
[24]	DING J, CHEN X, GAO Z, et al. Metabolism and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor apatinib in humans[J]. Drug Metab Dispos, 2013, 41(6): 1195-1210. DOI: 10.1124/dmd.112.050310.
[25]	GRETEN TF, MAUDA-HAVAKUK M, HEINRICH B, et al. Combined locoregional-immunotherapy for liver cancer[J]. J Hepatol, 2019, 70(5): 999-1007. DOI: 10.1016/j.jhep.2019.01.027.