摘要
目的探讨甲胎蛋白(AFP)反应评估酪氨酸激酶抑制剂(TKIs)联合程序性死亡受体1抑制剂(α‑PD‑1)治疗中晚期肝癌的抗肿瘤疗效以及预测患者预后的价值。方法采用回顾性队列研究方法。收集2020年3月至2022年7月福建医科大学孟超肝胆医院等我国9家医学中心收治的205例中晚期肝癌患者临床病理资料;男178例,女27例;年龄为(52±12)岁。基于治疗后6~8周AFP反应,将患者分为AFP反应(AFP水平与基线比较下降≥50%)和AFP无反应(AFP水平与基线比较下降<50%)。观察指标:(1)AFP反应评估抗肿瘤疗效。(2)患者预后比较。(3)患者预后影响因素分析。正态分布的计量资料以x±s表示。偏态分布的计量资料以M(范围)表示或M(Q1,Q3)表示。计数资料以绝对数表示,组间比较采用χ^(2)检验。Kaplan‑Meier法绘制生存曲线并计算生存率,采用Log‑Rank检验进行生存分析。单因素分析采用COX比例风险模型,多因素分析采用COX逐步回归。结果(1)AFP反应评估抗肿瘤疗效。205例肝癌患者治疗前AFP均为阳性,基线AFP水平为1560(219,3400)μg/L,均行TKIs联合α‑PD‑1治疗,治疗6~8周后AFP水平为776(66,2000)μg/L。205例患者治疗后,AFP反应88例,AFP无反应117例。参照实体瘤疗效评价标准1.1,AFP反应患者治疗后客观缓解率和疾病控制率分别为42.05%(37/88)和94.32%(83/88),AFP无反应患者上述指标分别为16.24%(19/117)和64.10%(75/117),两者上述指标比较,差异均有统计学意义(χ^(2)=16.846,25.950,P<0.05)。参照改良的实体瘤疗效评价标准,AFP反应患者治疗后客观缓解率和疾病控制率分别为69.32%(61/88)和94.32%(83/88),AFP无反应患者上述指标分别为33.33%(39/117)和64.10%(75/117),两者上述指标比较,差异均有统计学意义(χ^(2)=26.030,25.950,P<0.05)。(2)患者预后比较。205例患者治疗后均获得随访,随访时间为12.4(2.4~34.0)个月,中位无进展生存时间和总生存时间分别为5.5个月和17.8个月,1、2年无进展生存率分别为20.8%、7.2%,1、2年总生存率分别为68.7%、31.5%。AFP反应患者中位无进展生存时间为9.7个月,1、2年无进展生存率分别为39.6%、14.2%;AFP无反应患者中位无进展生存时间为3.7个月,1、2年无进展生存率分别为7.8%、2.0%;两者无进展生存情况比较,差异有统计学意义(χ^(2)=43.154,P<0.05)。AFP反应患者中位总生存时间未达到,1、2年总生存率分别为85.2%、56.3%;AFP无反应患者中位总生存时间为14.6个月,1、2年总生存率分别为56.3%、14.5%;两者总生存情况比较,差异有统计学意义(χ^(2)=33.899,P<0.05)。(3)患者预后影响因素分析。多因素分析结果显示:大血管侵犯、肝外转移、联合经肝动脉介入治疗、AFP反应是影响中晚期肝癌患者行TKIs联合α‑PD‑1治疗后无进展生存的独立因素(风险比=1.474,1.584,0.631,0.367,95%可信区间为1.069~2.033,1.159~2.167,0.446~0.893,0.261~0.516,P<0.05)。多因素分析结果显示:美国东部肿瘤协作组评分、大血管侵犯、肝外转移、AFP反应是影响中晚期肝癌患者行TKIs联合α‑PD‑1治疗后总生存的独立因素(风险比=1.347,1.914,1.673,0.312,95%可信区间为1.041~1.742,1.293~2.833,1.141~2.454,0.197~0.492,P<0.05)。结论治疗后6~8周的AFP反应可有效评估中晚期肝癌患者行TKIs联合α‑PD‑1治疗的抗肿瘤疗效。AFP反应是影响中晚期肝癌患者行TKIs联合α‑PD‑1治疗后无进展生存和总生存的独立因素。
Objective To investigate the evaluation efficacy and predictive prognostic value of alpha-fetoprotein(AFP)response in tyrosine kinase inhibitors(TKIs)in combination with PD-1 inhibitors(α-PD-1)for intermediate-to-advanced hepatocellular carcinoma(HCC).Methods The retrospective cohort study was conducted.The clinicopathological data of 205 patients with intermediate-to-advanced HCC who were admitted to 9 medical centers,including Mengchao Hepatobiliary Hospital of Fujian Medical University et al,from March 2020 to July 2022 were collected.There were 178 males and 27 females,aged(52±12)years.Based on AFP response at 6−8 weeks after treatment,patients were divided into the AFP response group(AFP level decreased by≥50%compared to baseline)and the AFP no response group(AFP level decreased by<50%compared to baseline).Observation indicators:(1)AFP response evaluation of anti-tumor efficacy;(2)comparison of patient prognosis;(3)analysis of factors affecting patient prognosis.Measurement data with normal distrubution were represented as Mean±SD,and measurement data with skewed distribution were represented as M(range)and M(Q1,Q3).Count data were described as absolute numbers,and comparison between groups was conducted using the chi-square test.The Kaplan-Meier method was used to draw survival curve and calculate survival rate,and the Log-Rank test was used for survival analysis.The COX proportional risk model was used for univariate analysis and the COX stepwise regression model was used for multivariate analysis.Results(1)AFP response evaluation of anti-tumor efficacy.Before treatment,all 205 patients were positive of AFP,with a baseline AFP level of 1560(219,3400)μg/L.All 205 patients were treated with TKIs in combination withα-PD-1,and the AFP level was 776(66,2000)μg/L after 6 to 8 weeks of treatment.Of the 205 patients,88 cases were classified as AFP response and 117 cases were classified as AFP no response.According to the response evaluation criteria in solid tumors version 1.1,the objective response rate(ORR)and disease control rate(DCR)were 42.05%(37/88)and 94.32%(83/88)in patients of the AFP response group and 16.24%(19/117)and 64.10%(75/117)in patients of the AFP no response group,showing significant differences between them(χ^(2)=16.846,25.950,P<0.05).According to the modified response evaluation criteria in solid tumors,the ORR and DCR were 69.32%(61/88)and 94.32%(83/88)in patients of the AFP response group and 33.33%(39/117)and 64.10%(75/117)in patients of the AFP no response group,showing significant differences between them(χ^(2)=26.030,25.950,P<0.05).(2)Comparison of patient prognosis.All 205 patients were followed up for 12.4(range,2.4−34.0)months after treatment.The median progression free survival time and total survival time were 5.5 months and 17.8 months,respectively.The 1-year,2-year progression free survival rates were 20.8%and 7.2%,and the 1-year,2-year overall survival rates were 68.7%and 31.5%,respectively.The median progression free survival time,1-year and 2-year progression free survival rates were 9.7 months,39.6%and 14.2%in patients of the AFP response group and 3.7 months,7.8%and 2.0%in patients of the AFP no response group,showing a significant difference in progression free survival between them(χ^(2)=43.154,P<0.05).The median overall survival time,1-year and 2-year overall survival rates were not reached,85.2%and 56.3%in patients of the AFP response group and 14.6 months,56.3%and 14.5%in patients of the AFP no response group,showing a significant difference in overall survival between them(χ^(2)=33.899,P<0.05).(3)Analysis of factors affecting patient prognosis.Results of multivariate analysis showed that invasion of large blood vessels,extrahepatic metastasis,combined hepatic artery intervention therapy,and AFP response were independent factors influencing progression free survival in patients with intermediate-to-advanced HCC who were treated with TKIs in combination withα-PD-1(hazard ratio=1.474,1.584,0.631,0.367,95%confidence interval as 1.069−2.033,1.159−2.167,0.446−0.893,0.261−0.516,P<0.05),and Eastern Cooperative Oncology Group score,invasion of large blood vessels,extrahepatic metastasis,and AFP response were independent factors influencing overall survival in patients with intermediate-to-advanced HCC who were treated with TKIs in combination withα-PD-1(hazard ratio=1.347,1.914,1.673,0.312,95%confidence interval as 1.041−1.742,1.293−2.833,1.141−2.454,0.197−0.492,P<0.05).Conclusions AFP response at 6−8 weeks after treatment can effectively evaluate anti-tumor efficacy of TKIs in combination withα-PD-1 for intermediate-to-advanced HCC.AFP response is the independent factor influencing progression free survival and overall survival in patients with intermediate-to-advanced HCC who were treated with TKIs in combination withα-PD-1.
作者
林孔英
陈清静
郭洛彬
杨云
陈宇峰
张建溪
魏复群
张辉
程智清
黎蕴通
王聪仁
江亚彬
林科灿
周伟平
曾永毅
Lin Kongying;Chen Qingjing;Guo Luobin;Yang Yun;Chen Yufeng;Zhang Jianxi;Wei Fuqun;Zhang Hui;Cheng Zhiqing;Li Yuntong;Wang Congren;Jiang Yabin;Lin Kecan;Zhou Weiping;Zeng Yongyi(Department of Hepatobiliary Surgery,Mengchao Hepatobiliary Hospital of Fujian Medical University,Fuzhou 350001,China;The Third Department of Hepatic Surgery,Eastern Hepatobiliary Surgery Hospital,Naval Medical University,Shanghai 200433,China;Department of General Surgery,Zhangzhou Municipal Hospital,Zhangzhou 363000,China;Department of Hepatobiliary Pancreatic Surgery,Xiamen Hospital of Traditional Chinese Medicine,Xiamen 361015,China;Department of Intervention,the First Affiliated Hospital of Fujian Medical University,Fuzhou 350001,China;Department of Hepatobiliary Pancreatic Surgery,Fujian Cancer Hospital,Fuzhou 350001,China;Department of Hepatobiliary Surgery,the Affiliated Hospital of Putian University,Putian 351100,China;Department of Hepatobiliary Surgery,Zhongshan Hospital of Xiamen University,Xiamen 361004,China;Department of Hepatobiliary Surgery,Quanzhou First Hospital Affiliated to Fujian Medical University,Quanzhou 362002,China;Department of Hepatobiliary Pancreatic Tumor Comprehensive Treatment,Mengchao Hepatobiliary Hospital of Fujian Medical University,Fuzhou 350001,China)
出处
《中华消化外科杂志》
CAS
CSCD
北大核心
2024年第2期248-256,共9页
Chinese Journal of Digestive Surgery
基金
国家自然科学基金(62275050)
福建省科技创新联合资金项目(2019Y9108)
福建省卫健委中青年科研重大项目(2021ZQNZD013)。
关键词
肝肿瘤
甲胎蛋白
酪氨酸激酶抑制剂
免疫检查点抑制剂
预后
Liver neoplasms
Alpha-fetoprotein
Tyrosine kinase inhibitor
Immune checkpoint inhibitor
Prognosis
