【作者】 刘博；

【导师】 王楠娅；

【作者基本信息】 吉林大学 ， 临床医学硕士（专业学位）， 2023， 硕士

【摘要】 背景:胆道癌(biliary tract carcinoma,BTC)是一种起源于胆道上皮细胞的恶性肿瘤,该病发病隐匿,早期无特异性临床表现,多数患者就诊时已处于晚期,预后差,治疗方法有限。近年来,以程序性细胞死亡受体1(programmed cell death-1,PD-1)/程序性细胞死亡配体1(programmed cell death-ligand 1,PD-L1)抑制剂为代表的免疫治疗药物进入临床后,晚期BTC治疗进入了免疫治疗的新时代。PD-1/PD-L1抑制剂联合化疗已经成为晚期BTC一线标准治疗方案。但大量晚期BTC患者经常因胆道梗阻、感染、体力状态差等相关因素无法耐受化疗。还有部分患者由于担心化疗带来的毒副反应等原因拒绝接受化疗。因此在实际临床工作中,对于无法按照规范指南接受一线治疗且仍有治疗需求的晚期BTC患者,亟需探索新的治疗方法来改善晚期BTC患者的预后、提高生活质量。仑伐替尼是一种多靶点酪氨酸激酶抑制剂,主要作用靶点包括血管内皮生长因子受体、成纤维细胞生长因子受体、血小板衍生生长因子受体α、黏附分子等。其可通过改善免疫抑制的微环境,从而与PD-1/PD-L1抑制剂发挥协同抗肿瘤效应。PD-1/PDL1抑制剂联合仑伐替尼治疗晚期BTC的II期临床研究结果显示出良好的抗肿瘤效果。因此对于不耐受化疗或者拒绝化疗的晚期BTC患者,临床上也有选择PD-1/PD-L1抑制剂联合仑伐替尼治疗的实际经验,但真实世界中PD-1/PD-L1抑制剂联合仑伐替尼一线治疗的有效性和安全性数据欠缺。因此,我们进行了本项回顾性研究,分析了PD-1/PD-L1抑制剂联合仑伐替尼一线治疗不耐受或者拒绝化疗的晚期BTC患者的疗效及安全性,为不耐受或者拒绝化疗的晚期BTC患者提供更多的治疗选择。方法:回顾性分析吉林大学第一医院肿瘤中心2022年2月至2022年9月使用PD-1/PD-L1抑制剂联合仑伐替尼一线治疗不耐受或者拒绝化疗的25例晚期BTC患者(仑伐替尼组)。以同时间段同中心使用PD-1/PD-L1抑制剂联合化疗一线治疗的26例晚期BTC患者作为对照(化疗组)。收集并记录患者基线资料、实验室指标、影像学检查资料、生存情况以及不良反应等。依据实体肿瘤疗效评价标准(RECIST 1.1)进行客观疗效评价,根据常见不良反应事件评价标准(CTCAE)5.0版进行不良反应评估,免疫治疗相关不良反应判定参照2021年CSCO免疫检查点抑制剂相关的毒性管理指南。主要研究终点为无进展生存期(progressionfree survival,PFS),次要研究终点为6个月总生存期(overall survival,OS)率、9个月OS率、客观缓解率(objective response rate,ORR)、疾病控制率(disease control rate,DCR)及不良反应。结果:1、两组患者的基线临床资料比较,除ECOG PS评分、有无腹水和ALT水平外,均具有可比性。仑伐替尼组7例(28.0%)患者ECOG PS评分为2分,而化疗组ECOG PS评分均为0-1分。仑伐替尼组7例(28.0%)患者有不同程度的腹水,而化疗组(3.8%)仅有1例患者存在少量腹水。2、截止末次随访,中位随访时间为10.2个月(95%CI:9.7-10.7)。仑伐替尼组和化疗组的ORR分别为16.0%和23.1%,P=0.777;DCR分别为52.0%和46.2%,P=0.676。仑伐替尼组和化疗组的中位PFS分别为9.5个月vs 5.1个月,P=0.454。两组的中位OS均未达到。仑伐替尼组6个月OS率和9个月OS率分别为82.0%和76.9%,化疗组6个月OS率和9个月OS率分别为87.4%和71.5%。3、单因素Cox分析显示患者ECOG PS评分,AST水平均可能影响患者PFS,其中ECOG PS评分(HR=3.388,95%CI:1.312-8.746,P=0.012)为影响PFS的独立危险因素。单因素Cox分析显示患者ECOG PS评分,Child-Pugh分级和TBil水平均可能影响患者OS,其中ECOG PS评分(HR=4.220,95%CI:1.131-15.742,P=0.032)为影响OS的独立危险因素。4、仑伐替尼组和化疗组不良反应发生率分别为72.0%和88.5%,P=0.625。仑伐替尼组不良反应主要为食欲减退、恶心呕吐、便秘和腹泻等胃肠道副作用。化疗组不良反应主要为乏力、食欲减退、恶心呕吐、骨髓抑制等常见化疗相关不良反应。仑伐替尼组3级不良反应有4例(16.0%),主要为乏力1例(4.0%)、手足皮肤反应1例(4.0%)、食欲减退1例(4.0%)和头晕1例(4.0%)。化疗组3级不良反应有4例(15.4%),主要为乏力1例(3.8%)和骨髓抑制3例(11.5%)。本研究中两组患者均无4级不良反应及相关不良反应死亡事件发生。结论:PD-1/PD-L1抑制剂联合仑伐替尼一线治疗不耐受或者拒绝化疗的晚期BTC患者具有一定的疗效,不良反应可控,可作为不耐受或者拒绝化疗的晚期BTC患者一线治疗的一种替代治疗。更多还原

【Abstract】 Background:Biliary tract carcinoma(BTC)is a malignant tumor originated from the epithelial cells lining the biliary tract.Due to insidious onset and non-specific clinical presentations,most patients are diagnosed at advanced stage with poor prognosis and limited therapeutic options.In recent years,the advent of immunotherapeutic agents such as programmed cell death-1(PD-1)/programmed cell death-ligand 1(PD-L1)inhibitors has brought the treatment for patients with advanced BTC into a new era.PD-1/PD-L1 inhibitors combined with chemotherapy have been recognized as the firstline standard treatment for advanced BTC patients.However,many advanced BTC patients are with biliary obstruction or infection,and in poor physical condition,resulting in intolerance to chemotherapy.In addition,some patients may refuse chemotherapy concerning about the toxicity.Therefore,there is an urgent need to develop new first-line treatments for advanced BTC patients who are unable to receive chemotherapy.Lenvatinib is a multi-target tyrosine kinase inhibitor with major targets of action including vascular endothelial growth factor receptor,fibroblast growth factor receptor,platelet derived growth factor receptor α,adhesion molecules and so on.It can play a synergistic role with PD-1/PD-L1 inhibitors by improving the immunosuppressive microenvironment.PD-1/PD-L1 inhibitors combined with lenvatinib for advanced BTC have also shown good anti-tumor effects in phase II clinical studies.There are also many clinical practices showing good efficacy of PD-1/PD-L1 inhibitors combined with lenvatinib for advanced BTC patients who are intolerant to or refuse chemotherapy.However,data on the efficacy and safety of PD-1/PD-L1 inhibitors combined with lenvatinib as first-line treatment in the real world are lack.Therefore,we conducted this retrospective study to investigate the efficacy and safety of PD-1/PD-L1 inhibitors combined with lenvatinib as the first-line treatment for patients with advanced BTC who are intolerant to or refuse chemotherapy,which may provide more treatment options for patients with advanced BTC who are intolerant to or refuse chemotherapy.Methods:We retrospectively analyzed 25 advanced BTC patients who were intolerant to or refused chemotherapy receiving PD-1/PD-L1 inhibitors combined with lenvatinib as the first-line treatment from February 2022 to September 2022 at the First Hospital of Jilin University Oncology Center(lenvatinib group).Twenty-six advanced BTC patients receiving PD-1/PD-L1 inhibitors combined with chemotherapy at the same center during the same period were used as controls(chemotherapy group).Baseline characteristic,laboratory data,imaging files,survival and adverse events were collected.Objective efficacy evaluation was performed according to Response Evaluation Criteria in Solid Tumors(RECIST 1.1),and adverse reactions were evaluated according to the Common Terminology Criteria for Adverse Events(CTCAE)version 5.0.Immunotherapy-related adverse reactions were determined according to the 2021 CSCO guidelines for the management of toxicity associated with immune checkpoint inhibitors.The primary endpoint of our study was progression-free survival(PFS)and the secondary endpoints included overall survival(OS)rates at 6th and 9th months,objective response rate(ORR),disease control rate(DCR)and adverse events.Results:1.The baseline characteristics were virtually balanced in two groups except for ECOG PS score,presence of ascites and ALT levels.Seven patients(28.0%)in the lenvatinib group had an ECOG PS score of 2,while all patients in the chemotherapy group had an ECOG PS score of 0-1.Seven patients(28.0%)in the lenvatinib group had presences of ascites in different degree,while only one patient in the chemotherapy group(3.8%)had a small amount of ascites.2.Up to the last follow-up,the median follow-up time was 10.2 months(95% CI:9.7-10.7).The ORR in the lenvatinib group and chemotherapy group were 16.0 % and23.1%,respectively,(P=0.777);DCR was 52.0% and 46.2%,respectively,(P=0.676).The median PFS in the lenvatinib group and chemotherapy group was 9.5 months vs5.1 months,respectively,(P=0.454).The median OS in both groups was not reached.The 6-month OS rate and 9-month OS rate were 82.0% and 76.9% in the lenvatinib group,and the 6-month OS rate and 9-month OS rate were 87.4% and 71.5% in the chemotherapy group,respectively.3.Univariate Cox analysis showed that patients’ ECOG PS score and AST level may affect PFS,with ECOG PS score(HR=3.388,95% CI: 1.312-8.746,P=0.012)being an independent risk factor for PFS.Univariate Cox analysis showed that patient’ECOG PS score,Child-Pugh grade and TBil level may affect OS,with ECOG PS score(HR = 4.220,95% CI: 1.131-15.742,P=0.032)being an independent risk factor for OS.4.The adverse events rates in the lenvatinib and chemotherapy groups were 72.0%and 88.5%,respectively,(P=0.625).The adverse events of lenvatinib group were frequently presented in gastrointestinal tract such as anorexia,nausea and vomiting,constipation and diarrhea.Adverse events in the chemotherapy group were mainly fatigue,anorexia,nausea and vomiting,myelosuppression and other common chemotherapy-related side effects.There were 4 cases(16.0%)adverse events of grade3 in the lenvatinib group,including 1(4.0%)fatigue,1(4.0%)hand-foot skin reaction,1(4.0%)anorexia and 1(4.0%)dizziness.There were 4 cases(15.4%)adverse events of grade 3 in the chemotherapy group,including 1(3.8%)fatigue and 3(11.5%)myelosuppression.No grade 4 adverse event and death case associated with side effect was observed in this study.Conclusion:PD-1/PD-L1 inhibitors combined with lenvatinib have shown good efficacy and controllable adverse events as the first-line treatment for patients with advanced BTC who are intolerant to or refuse chemotherapy,which are expected to be an alternative treatment for first-line treatment of advanced BTC patients who are intolerant to or refuse chemotherapy.更多还原