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Article(id=1239174992009687555, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1239174986137661844, articleNumber=null, orderNo=null, doi=10.14109/j.cnki.xyylc.2024.04.07, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1662566400000, receivedDateStr=2022-09-08, revisedDate=null, revisedDateStr=null, acceptedDate=1709222400000, acceptedDateStr=2024-03-01, onlineDate=1773371940853, onlineDateStr=2026-03-13, pubDate=1713974400000, pubDateStr=2024-04-25, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1773371940853, onlineIssueDateStr=2026-03-13, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1773371940853, creator=13701087609, updateTime=1773371940853, updator=13701087609, issue=Issue{id=1239174986137661844, tenantId=1146029695717560320, journalId=1205117082300743687, year='2024', volume='43', issue='4', pageStart='241', pageEnd='320', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1773371939453, creator=13701087609, updateTime=1773372128807, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1239175780396233704, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1239174986137661844, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1239175780396233705, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1239174986137661844, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=273, endPage=279, ext={EN=ArticleExt(id=1239174992273928724, articleId=1239174992009687555, tenantId=1146029695717560320, journalId=1205117082300743687, language=EN, title=Cost-utility analysis of camrelizumab combined with apatinib in first-line treatment of advanced unresectable hepatocellular carcinoma, columnId=1207314218647392369, journalTitle=Chinese Journal of New Drugs and Clinical Remedies, columnName=Original Article, runingTitle=null, highlight=null, articleAbstract=
AIM

To evaluate the cost-utility of camrelizumab in combination with apatinib and sorafenib in the first-line treatment of advanced unresectable hepatocellular carcinoma（uHCC）.

METHODS

Based on the clinical trial data of CARES-310, a partitioned survival model was constructed to simulate the cost and outcomes of camrelizumab in combination with apatinib and sorafenib in the first-line treatment of advanced uHCC, and the incremental cost-effectiveness ratio（ICER）of the two strategies was calculated using the cost-utility analysis from the perspective of Chinese medical and health system. Single factor sensitivity analysis and probabilistic sensitivity analysis were used to evaluate the stability of the results.

RESULTS

The total cost of camrelizumab in combination with apatinib regimen was 285 459 yuan, and 0.999 QALYs was obtained. The total cost of sorafenib regimen was 238 948 yuan, and 0.726 QALYs was obtained. The ICER of camrelizumab in combination with apatinib regimen against sorafenib regimen was 170 112 yuan·QALY-1, which did not exceed the willingness-to-pay threshold of 257 094 yuan·QALY-1 in China. The results of sensitivity analysis indicated that the basic analysis was robust.

CONCLUSION

From the perspective of Chinese healthcare system, camrelizumab combined with apatinib is cost-effectiveness compared with sorafenib in the first-line treatment of advanced uHCC.

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目的

评价卡瑞利珠单抗联合阿帕替尼对比索拉非尼一线治疗晚期不可切除的肝细胞癌（uHCC）的经济性。

方法

从我国医疗卫生体系角度出发，基于CARES-310临床研究数据，构建分区生存模型对卡瑞利珠单抗联合阿帕替尼对比索拉非尼一线治疗uHCC的成本和产出进行模拟，采用成本-效用分析法计算两种方案的增量成本-效果比（ICER），并采用单因素敏感性分析和概率敏感性分析检验结果的稳定性。

结果

卡瑞利珠单抗联合阿帕替尼方案的总成本为285 459元，可获得0.999质量调整生命年（QALY）；索拉非尼方案的总成本为238 948元，可获得0.726 QALYs，卡瑞利珠单抗联合阿帕替尼对比索拉非尼的ICER为170 112元·QALY-1，低于意愿支付阈值（257 094元·QALY-1）。敏感性分析结果表明基础分析结果稳健。

结论

从我国医疗卫生体系角度出发，相较于索拉非尼，卡瑞利珠单抗联合阿帕替尼一线治疗晚期uHCC具有经济性。

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张惠娟
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蒋媛，女，副主任药师，硕士，主要从事药物经济学、合理用药研究，E-mail: 。

张惠娟，女，主任药师，硕士，主要从事药事管理研究，Phn: 86-22-27557096

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蒋媛，女，副主任药师，硕士，主要从事药物经济学、合理用药研究，E-mail: 。

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蒋媛，女，副主任药师，硕士，主要从事药物经济学、合理用药研究，E-mail: 。

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张惠娟，女，主任药师，硕士，主要从事药事管理研究，Phn: 86-22-27557096

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Research progress in immune microenvironment and therapy of hepatocellular carcinoma[J].Prog Pharm Sci, 2022, 46（8）: 588-602., articleTitle=Research progress in immune microenvironment and therapy of hepatocellular carcinoma, refAbstract=null)], funds=[Fund(id=1239213764629811718, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239174992009687555, awardId=2022YJ025, language=CN, fundingSource=天津市人民医院科研项目(2022YJ025), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1239213759118496037, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239174992009687555, xref=1., ext=[AuthorCompanyExt(id=1239213759126884647, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239174992009687555, companyId=1239213759118496037, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1.Department of Pharmacy, Tianjin Union Medical Center, TIANJIN 300121, China), AuthorCompanyExt(id=1239213759135273256, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239174992009687555, companyId=1239213759118496037, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1.天津市人民医院 药学部，天津　300121)]), AuthorCompany(id=1239213759214965040, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239174992009687555, xref=2., ext=[AuthorCompanyExt(id=1239213759219159345, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239174992009687555, companyId=1239213759214965040, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.Clinical Medical College, Tianjin Medical University, TIANJIN 300270, China), AuthorCompanyExt(id=1239213759231742259, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239174992009687555, companyId=1239213759214965040, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.天津医科大学 临床医学院，天津　300270)])], figs=[ArticleFig(id=1239213761228231092, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239174992009687555, language=EN, label=null, caption=null, figureFileSmall=Gr5Ts/90HBqfq2iwJu1+mw==, figureFileBig=qzoVOIypDbIMvpr7VtaVYA==, tableContent=null), ArticleFig(id=1239213761349865917, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239174992009687555, language=CN, label=图1, caption=分区生存模型示意图

PFS：无进展生存期，PD：疾病进展，Death：死亡

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A:卡瑞利珠单抗联合阿帕替尼组总生存期（OS）曲线, B:卡瑞利珠单抗联合阿帕替尼组无进展生存期（PFS）曲线, C：索拉非尼组OS曲线，D：索拉非尼组PFS曲线

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PD：疾病进展，PFS：无进展生存期，ICER：增量成本-效果比，QLAY：质量调整生命年

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WTP：意愿支付，QLAY：质量调整生命年

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WTP：意愿支付，QLAY：质量调整生命年

, figureFileSmall=+VA2ETXdgR5q754dK7qhTQ==, figureFileBig=Atwy9Rxfk4pTLK3ytCGOBw==, tableContent=null), ArticleFig(id=1239213763782562277, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239174992009687555, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
组别生存曲线拟合分布Weibull分布指数分布Gaussian分布log-logistic分布log-normal分布
卡瑞利珠单抗联合阿帕替尼OSAIC11.45058.7099.39734.79336.692
BIC12.58059.27410.52735.92337.822
PFSAIC4.60219.6986.55920.64212.149
BIC4.18519.4906.14220.22611.732
索拉非尼OSAIC11.67352.01722.61236.30029.243
BIC12.80452.58223.74237.43030.373
PFSAIC17.14114.24217.73417.88717.752
BIC16.72414.03417.31717.47017.335
), ArticleFig(id=1239213763891614185, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239174992009687555, language=CN, label=表1, caption=

两组患者生存曲线不同分布的AIC、BIC值

, figureFileSmall=null, figureFileBig=null, tableContent=
组别生存曲线拟合分布Weibull分布指数分布Gaussian分布log-logistic分布log-normal分布
卡瑞利珠单抗联合阿帕替尼OSAIC11.45058.7099.39734.79336.692
BIC12.58059.27410.52735.92337.822
PFSAIC4.60219.6986.55920.64212.149
BIC4.18519.4906.14220.22611.732
索拉非尼OSAIC11.67352.01722.61236.30029.243
BIC12.80452.58223.74237.43030.373
PFSAIC17.14114.24217.73417.88717.752
BIC16.72414.03417.31717.47017.335
), ArticleFig(id=1239213763983888877, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239174992009687555, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
组别生存曲线参数分布参数值
卡瑞利珠单抗联合阿帕替尼OS
PFS		Gaussian
Weibull		λ=6.460，γ=15.536
λ=6.069，γ=1.829
索拉非尼OSWeibullλ=15.644，γ=2.119
PFS指数分布λ=3.947，γ=1.000
), ArticleFig(id=1239213764080357876, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239174992009687555, language=CN, label=表2, caption=

两组患者生存曲线最优拟合分布及参数值

, figureFileSmall=null, figureFileBig=null, tableContent=
组别生存曲线参数分布参数值
卡瑞利珠单抗联合阿帕替尼OS
PFS		Gaussian
Weibull		λ=6.460，γ=15.536
λ=6.069，γ=1.829
索拉非尼OSWeibullλ=15.644，γ=2.119
PFS指数分布λ=3.947，γ=1.000
), ArticleFig(id=1239213764176826872, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239174992009687555, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
参数单位价格频次敏感性分析范围分布类型
药品费用/元
卡瑞利珠单抗（每支200 mg）2 928200 mg，每2周1次±20%Gamma
阿帕替尼（每片250 mg）104.7250 mg，qd±20%Gamma
索拉非尼（每片200 mg）22.8~95400 mg，bid±20%Gamma
瑞戈非尼（每片40 mg）172.5160 mg，qd±20%Gamma
住院费用/元每周期1次（5 d）
医师诊察费100
一次性材料费87.5
床位费340
护理费137.5
实验室检查费/元每周期1次
血常规320
尿常规80
生化299
肿瘤标志物365
影像检查费/元340每3周期1次
首次诊断费/元5 6951次
疾病排除检查费/元6831次
不良反应治疗费/元
高血压408.838%a，15%bBeta
天冬氨酸转氨酶升高/丙氨酸转氨酶升高271.716%a，5%bBeta
蛋白尿2 588.66%aBeta
腹泻564.55%bBeta
中性粒细胞计数下降15 467.26%aBeta
血小板计数下降33 906.111%a，1%bBeta
掌跖红肿综合征930.212%a，15%bBeta
效用
PFS状态0.76±20%Beta
PD状态0.68±20%Beta
贴现率5%0~8%Beta
), ArticleFig(id=1239213764264907260, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239174992009687555, language=CN, label=表3, caption=

模型参数基础值及变化范围

, figureFileSmall=null, figureFileBig=null, tableContent=
参数单位价格频次敏感性分析范围分布类型
药品费用/元
卡瑞利珠单抗（每支200 mg）2 928200 mg，每2周1次±20%Gamma
阿帕替尼（每片250 mg）104.7250 mg，qd±20%Gamma
索拉非尼（每片200 mg）22.8~95400 mg，bid±20%Gamma
瑞戈非尼（每片40 mg）172.5160 mg，qd±20%Gamma
住院费用/元每周期1次（5 d）
医师诊察费100
一次性材料费87.5
床位费340
护理费137.5
实验室检查费/元每周期1次
血常规320
尿常规80
生化299
肿瘤标志物365
影像检查费/元340每3周期1次
首次诊断费/元5 6951次
疾病排除检查费/元6831次
不良反应治疗费/元
高血压408.838%a，15%bBeta
天冬氨酸转氨酶升高/丙氨酸转氨酶升高271.716%a，5%bBeta
蛋白尿2 588.66%aBeta
腹泻564.55%bBeta
中性粒细胞计数下降15 467.26%aBeta
血小板计数下降33 906.111%a，1%bBeta
掌跖红肿综合征930.212%a，15%bBeta
效用
PFS状态0.76±20%Beta
PD状态0.68±20%Beta
贴现率5%0~8%Beta
), ArticleFig(id=1239213764361376256, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239174992009687555, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
治疗方案总成本/元增量成本/元效果/QALYs增量效果/QALYsICER/元·QALY-1
卡瑞利珠单抗联合阿帕替尼285 45946 5110.9990.273170 112
索拉非尼238 9480.726
), ArticleFig(id=1239213764462039556, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239174992009687555, language=CN, label=表4, caption=

基础分析结果

, figureFileSmall=null, figureFileBig=null, tableContent=
治疗方案总成本/元增量成本/元效果/QALYs增量效果/QALYsICER/元·QALY-1
卡瑞利珠单抗联合阿帕替尼285 45946 5110.9990.273170 112
索拉非尼238 9480.726
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卡瑞利珠单抗联合阿帕替尼一线治疗晚期不可切除肝细胞癌的成本-效用分析
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蒋媛 1 , 朱盈盈 2 , 张惠娟 1
中国新药与临床杂志 | 论著 2024,43(4): 273-279
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中国新药与临床杂志 | 论著 2024, 43(4): 273-279
卡瑞利珠单抗联合阿帕替尼一线治疗晚期不可切除肝细胞癌的成本-效用分析
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蒋媛1 , 朱盈盈2, 张惠娟1
作者信息
  • 1.天津市人民医院 药学部，天津　300121
  • 2.天津医科大学 临床医学院，天津　300270

    • 蒋媛，女，副主任药师，硕士，主要从事药物经济学、合理用药研究，E-mail: 。

    张惠娟，女，主任药师，硕士，主要从事药事管理研究，Phn: 86-22-27557096

通讯作者:

张惠娟
Cost-utility analysis of camrelizumab combined with apatinib in first-line treatment of advanced unresectable hepatocellular carcinoma
Yuan JIANG1 , Ying-ying ZHU2, Hui-juan ZHANG1
Affiliations
  • 1.Department of Pharmacy, Tianjin Union Medical Center, TIANJIN 300121, China
  • 2.Clinical Medical College, Tianjin Medical University, TIANJIN 300270, China
出版时间: 2024-04-25 doi: 10.14109/j.cnki.xyylc.2024.04.07
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摘要
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目的

评价卡瑞利珠单抗联合阿帕替尼对比索拉非尼一线治疗晚期不可切除的肝细胞癌（uHCC）的经济性。

方法

从我国医疗卫生体系角度出发，基于CARES-310临床研究数据，构建分区生存模型对卡瑞利珠单抗联合阿帕替尼对比索拉非尼一线治疗uHCC的成本和产出进行模拟，采用成本-效用分析法计算两种方案的增量成本-效果比（ICER），并采用单因素敏感性分析和概率敏感性分析检验结果的稳定性。

结果

卡瑞利珠单抗联合阿帕替尼方案的总成本为285 459元，可获得0.999质量调整生命年（QALY）；索拉非尼方案的总成本为238 948元，可获得0.726 QALYs，卡瑞利珠单抗联合阿帕替尼对比索拉非尼的ICER为170 112元·QALY-1，低于意愿支付阈值（257 094元·QALY-1）。敏感性分析结果表明基础分析结果稳健。

结论

从我国医疗卫生体系角度出发，相较于索拉非尼，卡瑞利珠单抗联合阿帕替尼一线治疗晚期uHCC具有经济性。

成本-效用分析  /  卡瑞利珠单抗  /  阿帕替尼  /  索拉非尼  /  肝细胞癌
AIM

To evaluate the cost-utility of camrelizumab in combination with apatinib and sorafenib in the first-line treatment of advanced unresectable hepatocellular carcinoma（uHCC）.

METHODS

Based on the clinical trial data of CARES-310, a partitioned survival model was constructed to simulate the cost and outcomes of camrelizumab in combination with apatinib and sorafenib in the first-line treatment of advanced uHCC, and the incremental cost-effectiveness ratio（ICER）of the two strategies was calculated using the cost-utility analysis from the perspective of Chinese medical and health system. Single factor sensitivity analysis and probabilistic sensitivity analysis were used to evaluate the stability of the results.

RESULTS

The total cost of camrelizumab in combination with apatinib regimen was 285 459 yuan, and 0.999 QALYs was obtained. The total cost of sorafenib regimen was 238 948 yuan, and 0.726 QALYs was obtained. The ICER of camrelizumab in combination with apatinib regimen against sorafenib regimen was 170 112 yuan·QALY-1, which did not exceed the willingness-to-pay threshold of 257 094 yuan·QALY-1 in China. The results of sensitivity analysis indicated that the basic analysis was robust.

CONCLUSION

From the perspective of Chinese healthcare system, camrelizumab combined with apatinib is cost-effectiveness compared with sorafenib in the first-line treatment of advanced uHCC.

cost-utility analysis  /  camrelizumab  /  apatinib  /  sorafenib  /  hepatocellular carcinoma
蒋媛, 朱盈盈, 张惠娟. 卡瑞利珠单抗联合阿帕替尼一线治疗晚期不可切除肝细胞癌的成本-效用分析. 中国新药与临床杂志, 2024 , 43 (4) : 273 -279 . DOI: 10.14109/j.cnki.xyylc.2024.04.07
Yuan JIANG, Ying-ying ZHU, Hui-juan ZHANG. Cost-utility analysis of camrelizumab combined with apatinib in first-line treatment of advanced unresectable hepatocellular carcinoma[J]. Chinese Journal of New Drugs and Clinical Remedies, 2024 , 43 (4) : 273 -279 . DOI: 10.14109/j.cnki.xyylc.2024.04.07
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2020年的统计数据显示，原发性肝癌是全球第六大常见癌症，其病死率高达8.3%[1]。原发性肝癌可分为肝细胞癌、肝内胆管细胞癌以及混合型肝癌等，其中肝细胞癌占75%~85%。我国是肝细胞癌的高危地区，2022年我国肝细胞癌发病人数和死亡人数分别有43.1万和41.2万人[2]，是名副其实的“肝癌大国”。在肝癌的治疗过程中，外科治疗往往是早期治疗的首选方法，通过肝切除术和肝移植术可以使肝癌患者获得长期生存[3]。但肝癌早期的发病症状往往不明显，许多患者在确诊时已经处于癌症的中晚期，丧失了手术治疗的机会。
2007年，索拉非尼被美国食品和药物管理局（FDA）批准上市，用于治疗不可切除的肝细胞癌（unresectable hepatocellular carcinoma，uHCC）[4]，成为首个获批一线治疗uHCC的靶向药物，但其所带来的疗效和总生存期（overall survival，OS）获益仍然有限。近年来，新上市的程序性细胞死亡受体1（programmed cell death 1 receptor，PD-1）/程序性细胞死亡受体配体1（programmed cell death 1 ligand 1，PD-L1）抑制剂联合抗血管生成药物治疗的方案获得了较好的治疗反应，明显延长了患者的OS。我国《原发性肝癌诊疗指南（2022年版）》[5]推荐的uHCC一线治疗方案包括阿替利珠单抗联合贝伐珠单抗、信迪利单抗联合贝伐珠单抗以及卡瑞利珠单抗联合阿帕替尼，均为1A级推荐。在阿替利珠单抗联合贝伐珠单抗、信迪利单抗联合贝伐珠单抗的相关研究中，中国患者有明显的临床获益，与索拉非尼单药治疗相比，患者的死亡风险及疾病进展风险降低均超过40%[6，7]。2023年7月，国际多中心Ⅲ期试验CARES-310研究公布的结果显示，卡瑞利珠单抗联合阿帕替尼一线治疗uHCC的中位OS达22.1个月，为目前uHCC一线治疗OS获益最多的方案[8]。目前，卡瑞利珠单抗及阿帕替尼均为国家医保谈判药品，但两药联合治疗的日费用仍高达313.8元，给社会医疗体系和患者带来较大的经济负担。本研究从中国医疗卫生体系的角度出发，基于CARES-310试验数据，评价了卡瑞利珠单抗联合阿帕替尼对比索拉非尼的经济性。
资料与方法
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目标人群
本研究的目标人群与CARES-310研究一致。该研究共入组543例患者，其中亚裔患者449例。患者的纳入标准包括：病理学确诊为uHCC；既往没有接受过uHCC的系统性治疗；肝功能Child-Pugh评分≤6分（A级）；巴塞罗那分期为B~C期；美国东部肿瘤协作组制定的活动状态评分为0或1分；至少有1个可测量病灶。患者的排除标准包括：有自身免疫疾病史；合并有乙型和丙型肝炎病毒感染；未经治疗或治疗不彻底的食管/胃静脉曲张出血或有高出血风险[8]。
治疗方案
卡瑞利珠单抗联合阿帕替尼组患者给予卡瑞利珠单抗200 mg，每2周1次+阿帕替尼250 mg，每日1次。索拉非尼组患者给予索拉非尼400 mg，每日2次。两组患者均持续用药至疾病进展（progressive disease, PD）或出现无法耐受的毒性反应。在治疗过程中如果出现PD，则转入二线治疗，由于CARES-310研究对二线治疗方案未进行具体说明，本研究根据已发表的文献[9，10]，假设两组患者均采用酪氨酸激酶抑制剂瑞戈非尼（160 mg，每日1次）作为二线治疗方案。
模型结构
基于CARES-310研究数据，建立分区生存模型（partitioned survival model，PSM）进行两种治疗方案的成本-效用分析。根据uHCC的发展规律，该模型假设患者存在3种不同的健康状态：无进展生存期（progressive free survival，PFS）、PD和死亡（Death），模型结构见图1。假设所有患者进入模型时均处于PFS状态，并且在1个周期中，只能从一个状态转换为另一个状态或保持不变（即PFS状态可转换为PD或Death状态，PD可转换为Death状态，但不可逆向转换）。同一患者在不同状态中均接受相应的药物治疗方案，若发生PD，两组患者均接受相应的二线治疗直至死亡。基于CARES-310研究，本研究将模型的循环周期设置为4周。因模型运行10年后两组患者几乎全部处于Death状态，故本研究将研究时限设置为10年。参考《中国药物经济学评价指南（2020）》[11]，该模型采用5%的贴现率对成本和健康产出进行贴现，通过计算两种方案的成本、质量调整生命年（quality adjusted life years，QALY）和增量成本-效果比（incremental cost-effectiveness ratio，ICER）来判断其经济性。本研究的意愿支付（willingness to pay，WTP）阈值为中国2022年人均国内生产总值（85 698元）的3倍，即257 094元·QALY-1[12]。本研究采用R4.0.5软件模拟生存曲线，采用Excel 2019进行PSM的构建和成本-效用分析。
生存分析
在进行经济学评价时，由于随访时间有限，通常需要对所报道的生存曲线进行外推以获得所需生存数据。本研究使用GetData Graph Digitizer v2.25软件在CARES-310研究报道的原始PFS曲线和OS曲线上取点，得到不同时间点上处于PFS和OS的人数，并对该样本基础数据进行整理，通过R4.0.5软件，采用Weibull、指数、Gaussian、log-logistic、log-normal等参数分布对生存数据进行拟合[13]，得到新的PFS曲线和OS曲线，生存曲线的参数拟合结果见表1。根据赤池信息准则（AIC）及贝叶斯信息准则（BIC）判断最优拟合分布，结果见表2，参数拟合后获得的生存曲线见图2。
成本和效用值数据
由于本研究基于我国医疗卫生体系的角度，因此只纳入直接医疗成本，包括CARES-310研究所涉及的药品费用、住院费用、实验室检查费和影像检查费、首次诊断费、疾病排除检查费及不良反应治疗费等。其中，计算药品费用时，给药剂量按照中国人的平均体重（65 kg）和体表面积（1.72 m2）计[14]；住院费用主要指住院治疗期间的诊断及治疗费用，包括医师诊察费、护理费、一次性材料费及床位费等，费用以5 d计（主要参考我院肝癌患者周期性化疗或免疫治疗的平均住院日）；实验室检查费包括血尿常规、生化检查和肿瘤标志物检测等；影像检查费主要指腹部电子计算机断层扫描（CT）检查费；首次诊断费包括病理诊断和PD-1表达检测费用；疾病排除检查包括自身免疫疾病和肝炎分型检查；治疗相关的不良反应仅考虑3级以上不良反应，不良反应及其发生率均来源于CARES-310研究，包括高血压、天冬氨酸转氨酶/丙氨酸转氨酶升高、蛋白尿、腹泻、血液系统不良反应（中性粒细胞计数及血小板计数下降等）及掌跖红肿综合征等。另外，若肿瘤发生进展，则两组均采用瑞戈非尼进行二线治疗，其主要不良反应类别及发生率均与索拉非尼相似[15]。本研究中的药品价格来源于天津市医药采购中心公布的药品挂网价格的中位数，国家组织的集中带量采购中选药品以集中带量采购价格计；住院治疗期间诊断及治疗费用参考天津市三级医疗机构医疗服务项目价格；不良反应管理成本和PD-1表达检测费用参考已发表文献[14，16-19]。两组患者在PFS状态的基线效用值均为0.76，在PD状态下的基线效用值均为0.68[20]，主要的模型参数基础值及变化范围见表3。
敏感性分析
本研究采用单因素敏感性分析和概率敏感性分析来评价模型的稳定性。单因素敏感性分析参数范围见表3，结果采用飓风图展示。每个参数在特定分布（表3）下进行1 000次蒙特卡洛模拟分析其概率敏感性，以结果散点图和成本-效果可接受曲线展示。
结果
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基础分析结果
基础分析结果如表4所示。卡瑞利珠单抗联合阿帕替尼方案对比索拉非尼的ICER为170 112元·QALY-1，低于设定的WTP（257 094元·QALY-1），故认为卡瑞利珠单抗联合阿帕替尼组方案一线治疗晚期uHCC的经济性优于索拉非尼。
单因素敏感性分析
参考相关文献[14-20],单因素敏感性分析考察了7个参数，即卡瑞利珠单抗和索拉非尼的药品费用、PFS和PD状态效用值、贴现率以及两组的不良反应治疗费用，得到的结果见图3。对ICER影响最大的因素为贴现率，其次为PD状态效用值和卡瑞利珠单抗费用。但无论各参数如何变化，其对应的ICER值均低于我国的WTP。
概率敏感性分析结果
概率敏感性分析结果见图4，绝大部分的散点都落在第一象限，表示卡瑞利珠单抗联合阿帕替尼组能够获得更高的效用，但同时需要花费更高的成本，69.2%的散点落在阈值线的下方，表示在WTP为257 094元·QALY-1时，卡瑞利珠单抗联合阿帕替尼组对比索拉非尼组具有经济性的概率为69.2%。成本-效果可接受曲线（图5）显示，当WTP超过166 000元·QALY-1时，卡瑞利珠单抗联合阿帕替尼方案具有经济性的概率超过50%，且WTP越高，卡瑞利珠单抗联合阿帕替尼方案越具有经济性。
讨论
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肿瘤是免疫细胞与周围微环境相互作用的结果，因此，实现靶向免疫正常化是治疗肝癌的关键策略[21]。免疫治疗结合抗血管生成治疗,能有效改善免疫抑制微环境，使肝癌血管正常化，进而促进药物进入肿瘤组织，最终达到治疗目的。目前，多项Ⅲ期临床研究围绕免疫治疗联合抗血管生成治疗开展，将为晚期肝癌的一线治疗带来更多的选择。本研究临床数据来源于一项Ⅲ期国际多中心临床研究CARES-310[8]。该研究共纳入543例晚期肝癌患者，来自13个国家/地区的95个研究中心，其中449名为亚裔，来自中国、韩国等地。卡瑞利珠单抗联合阿帕替尼组中位OS为22.1个月，相较于索拉非尼组（15.2个月）获益显著，死亡风险降低了38%（风险比为0.62，95%置信区间为0.49~0.80，P<0.000 1），为我国患者提供了更加安全、有效的治疗新选择，已经成为我国《原发性肝癌诊疗指南（2022年版）》1A级推荐方案。本研究对卡瑞利珠单抗联合阿帕替尼对比索拉非尼治疗晚期uHCC的经济性进行了评价，结果表明，基于中国医疗卫生体系，卡瑞利珠单抗联合阿帕替尼的经济性更优。
但本研究存在一定的局限性：（1）本研究中的长期生存数据由短期临床数据外推获得，生存数据存在一定的不确定性，可能导致结果存在一定偏倚；（2）有关两组方案在治疗过程中产生的不良反应治疗费用，由于本研究只考虑了3级以上不良反应，这可能与实际情况存在一定的出入，但敏感性分析结果显示，不良反应治疗费用对结果的影响很小，本研究结果仍有一定参考价值；（3）使用卡瑞利珠单抗联合阿帕替尼方案治疗后，若病情进展，将使得后续方案的选择难度增加，如何鉴别产生耐药的药物目前尚仍缺乏有效的疗效标志物，导致后线治疗方案的选择多以医生的临床实践经验为基础，本研究中设置所有患者的二线治疗方案均为瑞戈非尼，也可能与临床实际存在差异；（4）本研究的健康效用值主要参考国外数据，由于不同种族之间患者的效用状态可能存在一定差异，今后还需进一步开展基于中国人群疾病相关的健康效用值研究，进而获得更具参考性的经济性评价结果。
综上所述，基于我国医疗卫生体系，卡瑞利珠单抗联合阿帕替尼一线治疗晚期uHCC较索拉非尼具有经济性。
基金
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  • 天津市人民医院科研项目(2022YJ025)
文献
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2024年第43卷第4期
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文章信息
doi: 10.14109/j.cnki.xyylc.2024.04.07
  • 接收时间：2022-09-08
  • 首发时间：2026-03-13
  • 出版时间：2024-04-25
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  • 收稿日期：2022-09-08
  • 录用日期：2024-03-01
基金
天津市人民医院科研项目(2022YJ025)
作者信息
    1.天津市人民医院 药学部，天津　300121
    2.天津医科大学 临床医学院，天津　300270

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张惠娟
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https://castjournals.cast.org.cn/joweb/zgxyylczz/CN/10.14109/j.cnki.xyylc.2024.04.07
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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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