白蛋白结合型紫杉醇一线治疗中国晚期胰腺癌的真实世界研究

A real-world study of first-line albumin-bound paclitaxel in the treatment of advanced pancreatic cancer in China

目的评价白蛋白结合型紫杉醇一线治疗中国晚期胰腺癌的临床疗效和安全性,并结合肿瘤组织二代高通量测序(NGS)检测等探索胰腺癌的预后相关分子。方法2018年12月至2020年12月在中国华东地区24家医院招募一线接受以白蛋白结合型紫杉醇为基础的治疗方案治疗的晚期胰腺癌患者229例。主要研究终点是总生存时间(OS)和治疗相关不良反应,次要研究终点是无进展生存时间(PFS)。对患者的手术切除或取活检的胰腺癌原发灶或转移灶组织标本进行NGS测序。结果229例患者的总体疾病控制率为79.9%,客观缓解率为36.3%。治疗期间常见的不良反应为贫血(159例)、白细胞减少(170例)、中性粒细胞减少(169例)、转氨酶升高(110例)和血小板减少(95例)等,其中3~4级中性粒细胞减少的发生率为12.2%(28/229)。中位随访时间为21.2个月,中位PFS为5.3个月,中位OS为11.2个月。其中70例局部晚期胰腺癌患者的中位PFS为7.4个月,中位OS为15.5个月;159例远处转移胰腺癌患者的中位PFS为3.9个月,中位OS为9.3个月。多因素Cox回归分析显示,临床分期(HR=1.47,95%CI:1.06~2.04)、原发肿瘤部位(HR=0.64,95%CI:0.48~0.86)、ECOG评分(HR=2.66,95%CI:1.53~4.65)和是否联合放疗(HR=0.65,95%CI:0.42~1.00)是接受以白蛋白结合型紫杉醇为基础治疗的晚期胰腺癌患者PFS的独立影响因素,原发肿瘤部位(HR=0.68,95%CI:0.48~0.95)、ECOG评分(HR=5.82,95%CI:3.14~10.82)和是否联合放疗(HR=0.58,95%CI:0.35~0.96)是接受以白蛋白结合型紫杉醇为基础治疗的晚期胰腺癌患者OS的独立影响因素。对87例有足量肿瘤组织标本的胰腺癌患者行NGS测序发现,中国晚期胰腺癌中基因突变频率居前4位的基因分别为KRAS(89.66%)、TP53(77.01%)、CDKN2A(32.18%)和SMAD4(21.84%)。CDKN2B、PTEN、FGF6和RBBP8基因突变增加晚期胰腺癌患者的死亡风险(均P<0.05)。结论在真实世界中,采用白蛋白结合型紫杉醇一线治疗中国晚期胰腺癌临床疗效确切,安全可靠。

Objective To observe and evaluate the clinical efficacy and safety of albumin-bound paclitaxel as first-line treatment for patients with advanced pancreatic cancer in China,and to explore the prognosis-related molecules in pancreatic cancer based on next-generation sequencing(NGS)of tumor tissues.Methods From December 2018 to December 2020,patients with locally advanced or metastatic pancreatic cancer were recruited to accept albumin-bound paclitaxel as first-line treatment in the oncology departments of 24 hospitals in East China.The primary endpoints were overall survival(OS)and treatment related adverse events,and the secondary endpoint was progression-free survival(PFS).Adverse effects were graded using Common Terminology Criteria for Adverse Events 5.0(CTCAE 5.0).NGS sequencing on the primary or metastatic tissue samples of pancreatic cancer obtained through surgical resection or biopsy was performed.Results This study recruited 229 patients,including 70 patients with locally advanced pancreatic cancer(LAPC)and 159 patients with metastatic pancreatic cancer(mPC).The disease control rate was 79.9%and the objective response rate is 36.3%.The common adverse effects during treatment were anaemia(159 cases),leucopenia(170 cases),neutropenia(169 cases),increased aminotransferases(110 cases),and thrombocytopenia(95 cases),and the incidence of grade 3-4 neutropenia is 12.2%(28/229).The median follow-up time was 21.2 months(95%CI:18.5-23.1 months).The median PFS(mPFS)was 5.3 months(95%CI:4.37-4.07 months)and the median OS(mOS)was 11.2 months(95%CI:9.5-12.9 months).The mPFS of patients with LAPC was 7.4 months(95%CI:6.6-11.2 months),and their mOS was 15.5 months(95%CI:12.6-NA months).The mPFS of patients with mPC was 3.9 months(95%CI:3.4-5.1 months),and their mOS was 9.3 months(95%CI:8.0-10.8 months).Multivariate Cox regression analysis showed that clinical stage(HR=1.47,95%CI:1.06-2.04),primary tumor site(HR=0.64,95%CI:0.48-0.86),Eastern Cooperative Oncology Group Performance Status(ECOG PS)score(HR=2.66,95%CI:1.53-4.65),and whether to combine radiotherapy(HR=0.65,95%CI:0.42-1.00)were independent influencing factors for the PFS of these patients.The primary tumor site(HR=0.68,95%CI:0.48-0.95),ECOG score(HR=5.82,95%CI:3.14-10.82),and whether to combine radiotherapy(HR=0.58,95%CI:0.35-0.96)were independent influencing factors of the OS of these patients.The most frequent gene mutations in these advanced stage pancreatic patients were KRAS(89.66%),TP53(77.01%),CDKN2A(32.18%),and SMAD4(21.84%)by NGS of tumor tissues from 87 pancreatic cancer patients with sufficient specimens.Further analysis revealed that mutations in CDKN2B,PTEN,FGF6,and RBBP8 genes were significantly associated with an increased risk of death(P<0.05).ConclusionAlbumin-bound paclitaxel as first-line treatment demonstrated feasible anti-tumor efficacy and manageable safety for patients with advanced pancreatic cancer in China.