立体定向放疗联合化疗不同治疗顺序对高龄局部晚期胰腺癌患者生存期的影响

Influence of combined treatment sequence of stereotactic body radiation therapy and chemotherapy on the survival of very elderly patients with locally advanced pancreatic cancer

目的探讨立体定向放疗(SBRT)联合化疗(CT)不同治疗顺序对高龄局部晚期胰腺癌(LAPC)患者生存期的影响。方法回顾性分析上海长海医院2012年1月至2016年12月间应用射波刀-SBRT治疗年龄≥60岁的LAPC患者资料,根据治疗的顺序分为先化疗后SBRT的CT+SBRT组、先SBRT后化疗的SBRT+CT组和SBRT前后均化疗的CT+SBRT+CT组。化疗方案为吉西他滨1 000 mg/m^2,第1、8、15天静脉滴注,每4周重复1次,或替吉奥(S-1) 80 mg/m^2,第1~8天口服,休息14 d,共应用6周期。推荐化疗时间6个月。放疗参数:中位总剂量36(30~45)Gy,中位单次剂量7(5~9)Gy,中位分割次数5(5~8)次,中位生物等效剂量(BED10)61.92(48~85.5)Gy。放化疗的间隔为2~3周。治疗后每3个月复查,主要观察指标为总生存期和中位无进展生存期(PFS),次要观察指标为不良反应。采用CTCAE 4.0分级标准评价化疗不良反应,采用RTOG/EORTC评分标准评估放疗不良反应。采用Kaplan-Meier法计算总生存率和PFS,采用单因素及多因素logistic模型分析影响患者生存期的独立危险因素。结果共260例患者纳入研究,其中CT+SBRT组28例,SBRT+CT组163例,CT+SBRT+CT组69例。入组患者中位总生存期为13.2(12.8~13.6)个月,中位PFS为8.2(7.7~8.7)个月。CT+SBRT组、SBRT+CT组、CT+SBRT+CT组患者总生存期分别为12.2(10.9~13.9)、13.4(12.9~13.9)、13.1(12.7~13.5)个月,差异无统计学意义(P=0.425);3组PFS分别为6.4(5.9~6.9)、8.3(7.8~8.8)、8.2(7.2~9.2)个月,差异有统计学意义(P=0.008)。单因素分析结果显示ECOG评分、全身炎症反应指数(SIRI)、治疗后CA19-9下降程度及BED10是影响总生存期的独立危险因素,多因素分析结果显示治疗后CA19-9下降程度及BED10是影响总生存期的独立危险因素。1例患者放疗发生3级十二指肠炎。先化疗患者的不良反应为3级中性粒细胞减少4例,3级胃肠道反应5例;后化疗患者的不良反应为3级中性粒细胞减少和(或)白细胞减少18例,3级腹痛、恶心、呕吐16例;前后均化疗患者的不良反应为3级中性粒细胞减少4例,3级腹痛、恶心5例。无4级及以上不良反应发生。结论对于高龄LAPC患者,无论SBRT前、SBRT后还是SBRT前后均化疗患者的总生存期相当,但SBRT后化疗组和SBRT前后均化疗组的PFS较SBRT前化疗组延长。

Objective To investigated the influence of different combined treatment sequence of stereotactic body radiation therapy (SBRT) and chemotherapy (CT) on the survival of very elderly patients with locally advanced pancreatic cancer (LAPC).Methods The data of LAPC patients ≥60 years old treated by CyberKnife SBRT at Shanghai Changhai Hospital from January 2012 to December 2016 was retrospectively analyzed. According to treatment sequences, patients were divided into three groups: CT+ SBRT group (first chemotherapy and then SBRT), SBRT+ CT group (first SBRT and then chemotherapy) and CT+ SBRT+ CT group (first chemotherapy, then SBRT and finally chemotherapy). Patients were recommended to receive a 6-month chemotherapy. Intravenous administration of 1 000 mg/m^2 gemcitabine was initiated on day 1, 8, and 15 every 4 weeks or S-1 was orally given at a dose of 80 mg/m^2 for 28 days followed by a 14-day rest, which repeated for 6 cycles. Radiotherapy parameters: the median total prescription dose was 36(30-45)Gy; the median per fraction dose was 7(5-9)Gy; the median number of fractions was 5(5-8) fractions; the median biological equivalent dose (BED10) were 61.92(48-85.5) Gy, respectively. The interval between SBRT and chemotherapy ranged from 2 to 3 weeks. Patients were followed every 3 months. The main outcome measures were overall survival (OS) and median progression free survival (PFS). Second outcome measure was adverse events. Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE 4.0) was employed to evaluate adverse events, and RTOG/EORTC was used to assess the adverse events of radiotherapy. Overall survival (OS) and PFS were calculated by Kaplan-Meier method. Univariate and multivariate logistic regression model were used to analyze the independent risk factors.Results A total of 260 patients were enrolled in the study, including 28 patients treated with CT+ SBRT, 163 patients undergoing SBRT+ CT and 69 patients treated with CT+ SBRT+ CT. The median OS and PFS were 13.2(95%CI 12.8-13.6)months and 8.2(95%CI7.7-8.7)months, respectively. OS in CT+ SBRT, SBRT+ CT and CT+ SBRT+ CT group was 12.2(10.9-13.9), 13.4(12.9-13.9)and 13.1(12.7-13.5)months, and the differences were not statistically significant(P=0.425). PFS in CT+ SBRT, SBRT+ CT and CT+ SBRT+ CT group was 6.4(5.9-6.9), 8.3(7.8-8.8) and 8.2(7.2-9.2)months, and the differences were statistically significant(P=0.008). In univariate analysis, ECOG, SIRI, the extent of decreased CA19-9 after treatment and BED10 were important factors of OS. In multivariate analysis, the CA19-9 response and BED10 were independent factors for OS. Multivariate analysis showed that the extent of decreased CA19-9 after treatment and BED10 were important factors of OS. In CT+ SBRT group, patients had lower ECOG score(χ^2=115.325, P<0.001) and earlier clinical staging(χ^2=24.788, P<0.001). In SBRT+ CT group, patients had advanced staging(χ^2=159.759, P<0.001) and lymph node metastasis(χ^2=40.925, P<0.001). Only 1 patient experienced grade 3 radiotherapy associated duodenitis. The adverse events of patients who were first treated by chemotherapy included grade 3 neutropenia in 4 patients and grade 3 gastrointestinal reaction in 5 patients. The adverse events of patients who were first treated by radiotherapy included grade 3 neutropenia or/and leucopenia in 18 patients and grade 3 abdominal pain, nausea or vomit in 16 patients. The adverse events of CT+ SBRT+ CT patients included grade 3 neutropenia or/and leucopenia in 4 patients and grade 3 abdominal pain or nausea in 5 patients. There was no grade ≥4 adverse events.Conclusions For very elderly patients with LAPC, the survival of patients who received pre-SBRT chemotherapy, post-SBRT chemotherapy and pre-and post-SBRT chemotherapy was comparable, but SBRT+ CT group and CT+ SBRT+ CT group had longer PFS than CT+ SBRT group.