程序性细胞死亡受体-1抑制剂治疗中晚期非病毒性相关肝癌的效果及安全性分析

刘浩楠; 王玉芹; 吴萌; 陆通; 赵阳; 韩正祥

doi:10.3969/j.issn.1001-5256.2022.12.015

程序性细胞死亡受体-1抑制剂治疗中晚期非病毒性相关肝癌的效果及安全性分析

DOI: 10.3969/j.issn.1001-5256.2022.12.015

刘浩楠^a,
王玉芹^b,
吴萌^a,
陆通^c,
赵阳^a,
韩正祥^a, , ,

a.
徐州医科大学附属医院肿瘤内科，江苏徐州 221000
b.
徐州医科大学附属医院普外科，江苏徐州 221000
c.
徐州医科大学附属医院消化内科，江苏徐州 221000

基金项目:

江苏省高层次卫生人才“六个一工程”A类项目 (LGY2020006)

伦理学声明：本研究于2022年6月23日得到徐州医科大学附属医院伦理委员会的批准，批准文号：XYFY2022-KL207-01。患者均在使用PD-1抑制剂之前签署知情同意书。

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：刘浩楠、王玉芹、韩正祥对研究的思路或设计有关键贡献；吴萌、陆通参与了研究数据的获取；刘浩楠、赵阳完成了数据分析；韩正祥修改文章关键内容并定稿。

详细信息

通信作者:
韩正祥，cnhzxyq@163.com

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出版历程
- 收稿日期: 2022-06-11
- 录用日期: 2022-07-12
- 出版日期: 2022-12-20

Effectiveness and safety of programmed cell death-1 inhibitor in the treatment of advanced non-HBV non-HCV-related hepatocellular carcinoma

a.
Department of Oncology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221000, China
b.
Department of General Surgery, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221000, China
c.
Department of Gastroenterology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221000, China

Research funding:

Jiangsu Province High-level Health Talents "Six Ones Project" Category A Project (LGY2020006)

More Information

Corresponding author: HAN Zhengxiang, cnhzxyq@163.com (ORCID: 0000-0002-1199-8983)

摘要

摘要: 目的研究国产程序性细胞死亡受体-1(PD-1)抑制剂在中晚期非病毒性相关肝癌(NBNC-HCC)中的临床疗效及不良反应。方法选取2019年6月—2022年2月徐州医科大学附属医院收治的使用国产PD-1抑制剂治疗的31例中晚期NBNC-HCC患者。分析患者疾病进展时间、客观缓解率、疾病控制率和不良反应发生情况。采用Kaplan-Meier法绘制生存曲线。结果在31例中晚期NBNC-HCC患者中，1例患者疗效评价为完全缓解，4例评价为部分缓解，6例评价为疾病稳定，20例评价为疾病进展，客观缓解率为16.1%，疾病控制率为35.5%，中位疾病进展时间为7.2(6.4~8.0)个月。不良反应发生率为61.30%，常见的不良反应为皮疹(29.03%)和高血压(22.58%)，所有患者均无4级不良反应和不良反应相关死亡事件发生。结论本研究提示中晚期NBNC-HCC患者对PD-1抑制剂治疗的反应可能较弱，但不良反应可控，未来仍需多中心前瞻性试验进一步验证。
- 肝肿瘤 /
- 程序性细胞死亡受体1 /
- 实体肿瘤疗效评价标准 /
- 药物相关性副作用和不良反应
Abstract: Objective To investigate the clinical effectiveness and adverse events of domestic programmed cell death -1 (PD-1) inhibitor in the treatment of advanced non-HBV non-HCV-related hepatocellular carcinoma (NBNC-HCC). Methods A totals of 31 patients with advanced NBNC-HCC who received domestic PD-1 inhibitor in the Affiliated Hospital of Xuzhou Medical University from June 2019 to February 2022 were retrospectively enrolled and their clinicopathological data were retrieved from their medical records and analyzed, i.e., the time to disease progression (TTP), disease control rate (DCR), objective response rate (ORR), and adverse events were recorded and statistically analyzed. The Kaplan-Meier method was used for survival analysis. Results Among these 31 patients, only one achieved the complete response and four achieved the partial response, and six had the stable disease, but 20 showed a disease progression, resulting in an ORR of 16.1% and a (DCR of 35.5%. The median TTP was 7.2 months [95% confidence interval: 6.4-8.0) months]. The incidence of adverse events was 61.30% and the common adverse events were skin rash (29.03%) and hypertension (22.58%). However, there was no grade 4 adverse reactions or related death in these patients. Conclusion Advanced NBNC-HCC patients had a relative weak response to the PD-1 inhibitor although the adverse events were controllable. Future multi-center prospective clinical trials are needed to validate the data.
- Liver Neoplasms /
- Programmed Cell Death 1 Receptor /
- Response Evaluation Criteria in Solid Tumors /
- Drug-Related Side Effects and Adverse Reactions

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图 1 TTP的生存曲线分析

Figure 1. Survival curve analysis of TTP

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图 2 OS的生存曲线分析

Figure 2. Survival curve analysis of OS

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表 1 入组患者的临床资料

Table 1. Clinical information of enrolled patients

项目	数值
年龄(岁)	57.13±11.55
性别[例(%)]
男	20(64.5)
女	11(35.5)
病因[例(%)]
NAFLD	24(77.4)
酒精性肝病	6(19.4)
自身免疫性肝病	1(3.2)
肿瘤大小[例(%)]
＜5 cm	13(41.9)
≥5 cm	18(58.1)
门静脉浸润[例(%)]
有	22(71.0)
无	9(29.0)
肝外转移[例(%)]
有	13(41.9)
无	18(58.1)
Child-Pugh分级[例(%)]
A	23(74.2)
B	8(25.8)
BCLC分期[例(%)]
B	5(16.1)
C	26(83.9)
ECOG评分[例(%)]
0	3(9.7)
1	22(71.0)
2	6(19.4)
既往治疗方式[例(%)]
TACE	19(61.3)
手术	6(19.4)
射频消融	4(12.9)
仑伐替尼	13(41.9)
索拉非尼	9(29.0)
阿帕替尼	6(19.4)
沙利度胺	8(25.8)
无	3(9.7)
PD-1抑制剂[例(%)]
卡瑞利珠单抗	18(58.1)
信迪利单抗	9(29.0)
特瑞普利单抗	4(12.9)
注：NAFLD，非酒精性脂肪性肝病；TACE，经导管动脉化疗栓塞术。

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表 2 入组患者的实验室资料

Table 2. Laboratory information of enrolled patients

项目	数值
AFP[例(%)]
＜400 ng/mL	13(42.0)
≥400 ng/mL	18(58.0)
AST(U/L)	36.87±14.64
ALT(U/L)	27.74±13.32
Alb(g/L)	39.55±5.01
TBil(μmol/L)	17.57±8.76
PT(s)	12.04±1.05

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表 3 入组患者肿瘤应答情况

Table 3. Tumor response of enrolled patients

项目	数值
CR(例)	1
PR(例)	4
SD(例)	6
PD(例)	20
ORR(%)	16.1(5/31)
DCR(%)	35.5(11/31)

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表 4 所有患者的不良反应情况

Table 4. Incidence of adverse reactions in all patients

项目	3级不良反应	总不良反应
皮疹[例(%)]	2(6.45)	9(29.03)
腹泻[例(%)]	1(3.23)	5(16.13)
疲劳[例(%)]	1(3.23)	6(19.35)
恶心[例(%)]	0	4(12.90)
蛋白尿[例(%)]	1(3.23)	5(16.13)
甲状腺炎[例(%)]	1(3.23)	3(9.68)
感觉异常[例(%)]	0	2(6.45)
高血压[例(%)]	3(9.68)	7(22.58)
口腔溃疡[例(%)]	0	4(12.90)
胆红素升高[例(%)]	0	2(6.45)
反应性皮肤毛细血管增生症[例(%)]	0	2(6.45)
ALT升高[例(%)]	0	4(12.90)
AST升高[例(%)]	1(3.23)	2(6.45)
肾上腺皮质功能减退[例(%)]	0	2(6.45)

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