高复发进展风险MIBC根治术后辅助化疗和辅助免疫治疗联合化疗的疗效

Therapeutic effects of adjuvant chemotherapy and adjuvant immunotherapy combined chemotherapy after radical cystectomy for MIBC with high risk of recurrence

目的探讨高复发进展风险(pT_(2)期伴淋巴结阳性,pT_(3~4a)期伴或不伴淋巴结阳性)肌层浸润性膀胱癌(MIBC)根治术后,辅助化疗和辅助免疫治疗联合化疗的疗效。方法回顾性分析2016年8月至2022年1月天津医科大学第二医院收治的217例高复发进展风险MIBC患者的临床资料。男183例(84.3%),女34例(15.7%);年龄(67.3±8.6)岁。217例均行根治性膀胱切除术+盆腔淋巴结清扫,根据术后接受辅助治疗情况分为观察组147例(67.7%)和治疗组70例(32.3%)。观察组和治疗组的年龄分别为(67.4±9.0)岁和(66.3±7.6)岁(P=0.14);术后病理分期T_(2)期伴淋巴结阳性分别为8例(5.4%)和6例(8.6%),T_(3~4a)期伴淋巴结阳性分别为34例(23.1%)和18例(25.7%),T_(3~4a)期不伴淋巴结阳性分别为105例(71.5%)和46例(65.7%)(P>0.05);肿瘤直径≥3cm分别为118例(80.3%)和54例(77.1%)(P>0.05),<3cm分别为29例(19.7%)和16例(22.9%)(P>0.05)。治疗组70例中,36例(16.6%)术后应用吉西他滨(1000mg/m^(2),第1、8天)和顺铂(75mg/m^(2),第2~4天)方案化疗(化疗组);34例(15.7%)应用免疫检查点抑制剂(静脉滴注信迪利单抗200mg或替雷利珠单抗200mg或特瑞普利单抗240mg,第1天)和白蛋白紫杉醇(200mg,第2天)方案治疗(免疫联合化疗组)。化疗组和免疫联合化疗组的年龄分别为(66.8±8.4)岁和(65.8±6.8)岁(P>0.05);术后病理分期T_(2)期伴淋巴结阳性分别为3例(8.3%)和3例(8.8%),T_(3~4a)期伴淋巴结阳性分别为6例(16.7%)和12例(35.3%),T_(3~4a)期不伴淋巴结阳性分别为27例(75.0%)和19例(55.9%)(P>0.05);肿瘤直径≥3cm分别为30例(83.3%)和10例(29.4%)(P>0.05),<3cm分别为6例(16.7%)和24例(70.6%)(P>0.05)。采用Kaplan-Meier法和多因素Cox回归分析观察组与治疗组术后1、3年的总生存期(OS),以及化疗组与免疫联合化疗组术后1、3年的无病生存期(DFS)。采用美国卫生及公共服务部发布的常见不良事件评价标准分析化疗组和免疫联合化疗组的并发症。结果本研究中位随访时间18.4(8.2,34.7)个月,观察组和治疗组中位随访时间分别为19.0(8.3,35.2)个月和17.5(7.9,33.2)个月;术后1年总生存率分别为76.2%和90.0%,差异有统计学意义(χ^(2)=6.92,P=0.009);术后3年总生存率分别为57.8%和82.9%,差异有统计学意义(χ^(2)=13.22,P<0.01)。观察组中位OS为35.9个月,治疗组中位OS未达到,差异有统计学意义(HR=2.51,95%CI1.36~4.65,P=0.003)。化疗组和免疫联合化疗组的中位随访时间分别为10.7(7.4,22.1)个月和14.4(6.3,40.7)个月;术后1年无病生存率分别为67.6%和91.2%,差异有统计学意义(χ^(2)=4.60,P=0.032);术后3年无病生存率分别为88.2%和55.6%,差异有统计学意义(χ^(2)=8.37,P=0.004)。化疗组中位DFS为27.7个月,免疫联合化疗组中位DFS未达到,差异有统计学意义(HR=3.39,95%CI1.46~7.89,P=0.016)。治疗组并发症分级1级140例,2级39例,3级8例,4级2例,5级0例。化疗组和免疫联合化疗组均出现5例≥3级不良反应,其中化疗组为2例贫血,2例血小板计数降低,1例中性粒细胞降低;免疫联合化疗组为1例贫血,1例血小板计数降低,2例中性粒细胞降低,1例-谷氨酰胺转移酶增高。化疗组和免疫联合化疗组≥3级不良反应发生率分别为13.9%(5/36)和14.7%(5/34),差异无统计学意义(χ^(2)=0.01,P=0.922)。结论对于高复发进展风险MIBC患者,术后行辅助治疗可明显延长OS。对于铂类化疗不耐受,或拒绝铂类辅助化疗的患者,可采用免疫检查点抑制剂联合白蛋白紫杉醇方案,作为根治性膀胱切除术后的辅助治疗方案,具有较好的疗效和安全性,不良反应可耐受。

Objective To explore the efficacy of adjuvant chemotherapy and adjuvant immunotherapy combined chemotherapy after radical cystectomy for muscle-invasive bladder cancer(MIBC)with high recurrence risk(pT_(2) with positive lymph nodes,and pT_(3~4a) with or without positive lymph nodes).Methods A retrospective analysis was conducted on clinical data of 217 patients with bladder cancer admitted to Tianjin Medical University Second Hospital from August 2016 to January 2022.Among them,183 were male(84.3%)and 34 were female(15.7%),with an average age of(67.3±8.6)years old.All 217 patients underwent radical cystectomy with pelvic lymph node dissection.Based on postoperative adjuvant treatment,the patients were divided into an observation group(147 cases,67.7%)and a treatment group(70 cases,32.3%).The observation group and treatment group had similar demographic and pathological characteristics.The age of the observation group and treatment group was(67.4±9.0)years and(66.3±7.6)years,respectively(P=0.14).The postoperative pathological stages T_(2)with lymph node positivity were observed in 8 cases(5.4%)in the observation group and 6 cases(8.6%)in the treatment group.For stages T_(3~4a) with lymph node positivity,there were 34 cases(23.1%)in the observation group and 18 cases(25.7%)in the treatment group.And there were 105 cases(71.5%)in the observation group and 46 cases(65.7%)in the treatment group of stages T_(3-4a) without lymph node positivity,respectively(P>0.05).Tumor diameter≥3 cm was found in 118 cases(80.3%)in the observation group and 54 cases(77.1%)in the treatment group(P>0.05),while tumor diameter<3 cm was observed in 29 cases(19.7%)in the observation group and 16 cases(22.9%)in the treatment group(P>0.05).In the treatment group,36 patients(16.6%)received postoperative chemotherapy with gemcitabine(1000 mg/m^(2),days 1 and 8)and cisplatin(75 mg/m,days 2 to 4)(chemotherapy group),while 34 patients(15.7%)received postoperative immunotherapy with checkpoint inhibitors(intravenous infusion of sintilimab 200 mg,terlizumab 200 mg,or toripalimab 240 mg on day 1)in combination with albumin-bound paclitaxel(200 mg on day 2)(immunotherapy combined chemotherapy group).The age of the chemotherapy group and immunotherapy combined chemotherapy group was(66.8±8.4)years and(65.8±6.8)years,respectively(P>0.05).Postoperative pathological stages T_(2) with lymph node positivity were observed in 3 cases(8.3%)in the chemotherapy group and 3 cases(8.8%)in the immunotherapy combined chemotherapy group(P>0.05).For stages T_(3~4a) with lymph node positivity,there were 6 cases(16.7%)in the chemotherapy group and 12 cases(35.3%)in the immunotherapy combined chemotherapy group.And there were 27 cases(75.0%)in the observation group and 19 cases(55.9%)in the treatment group of stages T_(3~4a) without lymph node positivity,respectively(P>0.05).Lymph node involvement was seen in 9 cases(25.0%)in the chemotherapy group and 15 cases(44.1%)in the immunotherapy combined chemotherapy group(P>0.05).Tumor diameter≥3 cm was found in 30 cases(83.3%))in the chemotherapy group and 10 cases(29.4%)in the immunotherapy combined chemotherapy group(P>0.05),while tumor diameter<3 cm was observed in 6 cases(16.7%)in the chemotherapy group and 24 cases(70.6%)in the immunotherapy combined chemotherapy group(P>0.05).Kaplan-Meier method and multivariate Cox regression test were used to analyze the overall survival(OS)at 1 and 3 years in the observation group and treatment group,as well as the disease-free survival(DFS)at 1 and 3 years in the chemotherapy group and immunotherapy combined chemotherapy group.Additionally,common adverse events were evaluated and compared between the chemotherapy group and immunotherapy combined chemotherapy group based on the criteria published by the U.S.Department of Health and Human Services.Results The median follow-up time in this study was 18.4(8.2,34.7)months.The median follow-up time in the observation group and treatment group was 19.0(8.3,35.2)months and 17.5(7.9,33.2)months,respectively.The l-year survival rate was significantly higher in the treatment group compared to the observation group(90.0%vs.76.2%,χ^(2)=6.92,P=0.009).Similarly,the 3-year survival rate was significantly higher in the treatment group compared to the observation group(82.9%vs.57.8%,χ^(2)=13.22,P<0.01).The median OS was 35.9 months in the observation group and was not reached in the treatment group,with a statistically significant difference(HR=2.51,95%CI 1.36-4.65,P=0.003).In the chemotherapy group and immunotherapy combined chemotherapy group,the median follow-up time was 10.7(7.4,22.1)months and 14.4(6.3,40.7)months,respectively.The 1-year disease-free survival rate was significantly higher in the immunotherapy combined chemotherapy group compared to the chemotherapy group(91.2%vs.67.6%,χ^(2)=4.60,P=0.032).The 3-year disease-free survival rate was significantly higher in the chemotherapy group compared to the immunotherapy combined chemotherapy group(88.2%vs.55.6%,χ^(2)=8.37,P=0.004).The median DFS was 27.7 months in the chemotherapy group and was not reached in the immunotherapy combined chemotherapy group,with a statistically significant dfference(HR=3.39,95%CI 1.46-7.89,P=0.016).The treatment group had complications classified as follows:140 cases of grade 1,39 cases of grade 2,8 cases of grade 3,2 cases of grade 4,and 0 case of grade 5 adverse reactions.In the chemotherapy group and the immunotherapy combined chemotherapy group,there were both 5 cases with adverse reactions of grade 3 or higher.Specifically,in the chemotherapy group,there were 2 cases of anemia,2 cases of decreased platelet count,and 1 case of decreased neutrophil count.In the immunotherapy combined chemotherapy group,there was 1 case of anemia,1 case of decreased platelet count,and 2 cases of decreased neutrophil count.Additionally,there was 1 case with elevated gammaglutamyltransferase(-GT)in the immunotherapy combined chemotherapy group.The incidence of adverse events of grade 3 or higher in the chemotherapy group and immunotherapy combined chemotherapy group was 13.9%and 14.7%,respectively,with no statistically significant difference(χ^(2)=0.01,P=0.922).ConclusionsAdjuvant therapy significantly prolongs the overall survival in high risk of recurrence for MIBC patients after radical cystectomy.For patients intolerant to platinum-based chemotherapy or refusing platinum-based adjuvant chemotherapy,immunotherapy with checkpoint inhibitors combined with albuminbound paclitaxel can be considered as an effective and well-tolerated adjuvant treatment after radical cystectomy.