ImportancePancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant tumor, and durable disease control is rare with the current standard of care, even for patients who undergo surgical resection.ObjectiveTo assess whether neoadjuvant modified 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFIRINOX) leads to early control of micrometastasis and improves survival.Design, Setting, and ParticipantsThis open-label, single-arm, phase 2 nonrandomized controlled trial for resectable PDAC was conducted at the Yale Smilow Cancer Hospital from April 3, 2014, to August 16, 2021. Pancreatic protocol computed tomography was performed at diagnosis to assess surgical candidacy. Data were analyzed from January to July 2023.InterventionsPatients received 6 cycles of neoadjuvant mFOLFIRINOX before surgery and 6 cycles of adjuvant mFOLFIRINOX. Whole blood was collected and processed to stored plasma for analysis of circulating tumor DNA (ctDNA) levels. Tumors were evaluated for treatment response and keratin 17 (K17) expression.Main Outcomes and MeasuresThe primary end point was 12-month progression-free survival (PFS) rate. Additional end points included overall survival (OS), ctDNA level, tumor molecular features, and K17 tumor levels. Survival curves were summarized using Kaplan-Meier estimator.ResultsOf 46 patients who received mFOLFIRINOX, 31 (67%) were male, and the median (range) age was 65 (46-80) years. A total of 37 (80%) completed 6 preoperative cycles and 33 (72%) underwent surgery. A total of 27 patients (59%) underwent resection per protocol (25 with R0 disease and 2 with R1 disease); metastatic or unresectable disease was identified in 6 patients during exploration. Ten patients underwent surgery off protocol. The 12-month PFS was 67% (90% CI, 56.9-100); the median PFS and OS were 16.6 months (95% CI, 13.3-40.6) and 37.2 months (95% CI, 17.5-not reached), respectively. Baseline ctDNA levels were detected in 16 of 22 patients (73%) and in 3 of 17 (18%) after 6 cycles of mFOLFIRINOX. Those with detectable ctDNA levels 4 weeks postresection had worse PFS (hazard ratio [HR], 34.0; 95% CI, 2.6-4758.6; P = .006) and OS (HR, 11.7; 95% CI, 1.5-129.9; P = .02) compared with those with undetectable levels. Patients with high K17 expression had nonsignificantly worse PFS (HR, 2.7; 95% CI, 0.7-10.9; P = .09) and OS (HR, 3.2; 95% CI, 0.8-13.6; P = .07).Conclusions and RelevanceThis nonrandomized controlled trial met its primary end point, and perioperative mFOLFIRINOX warrants further evaluation in randomized clinical trials. Postoperative ctDNA positivity was strongly associated with recurrence. K17 and ctDNA are promising biomarkers that require additional validation in future prospective studies.Trial RegistrationClinicalTrials.gov Identifier: NCT02047474

中文翻译：

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围手术期改良 FOLFIRINOX 用于可切除胰腺癌


重要性胰腺导管腺癌 (PDAC) 是一种侵袭性恶性肿瘤，即使对于接受手术切除的患者，在当前的护理标准下，持久的疾病控制也很少见。 目的评估新辅助改良 5-氟尿嘧啶、亚叶酸、奥沙利铂和伊立替康 (mFOLFIRINOX) 是否有效）导致微转移的早期控制并提高生存率。设计、设置和参与者这项针对可切除 PDAC 的开放标签、单臂、2 期非随机对照试验于 2014 年 4 月 3 日至 8 月 16 日在耶鲁大学 Smilow 癌症医院进行，2021 年。诊断时进行了胰腺方案计算机断层扫描，以评估手术候选资格。数据分析时间为 2023 年 1 月至 7 月。 干预措施 患者在手术前接受 6 个周期的新辅助 mFOLFIRINOX 治疗，并接受 6 个周期的辅助 mFOLFIRINOX 治疗。收集全血并加工成储存血浆，用于分析循环肿瘤 DNA (ctDNA) 水平。评估肿瘤的治疗反应和角蛋白 17 (K17) 表达。主要结果和措施主要终点是 12 个月无进展生存 (PFS) 率。其他终点包括总生存期 (OS)、ctDNA 水平、肿瘤分子特征和 K17 肿瘤水平。使用Kaplan-Meier估计器总结生存曲线。 结果接受mFOLFIRINOX的46名患者中，31名（67%）为男性，中位（范围）年龄为65（46-80）岁。总共 37 例 (80%) 完成了 6 个术前周期，33 例 (72%) 接受了手术。共有 27 名患者 (59%) 根据方案接受了切除术（25 名患者患有 R0 疾病，2 名患者患有 R1 疾病）；在探查过程中，6 名患者发现了转移性或不可切除的疾病。十名患者接受了方案外的手术。 12 个月的 PFS 为 67%（90% CI，56.9-100）；中位 PFS 和 OS 分别为 16.6 个月（95% CI，13.3-40.6）和 37.2 个月（95% CI，17.5-未达到）。在 6 个周期的 mFOLFIRINOX 治疗后，22 名患者中的 16 名 (73%) 和 17 名患者中的 3 名 (18%) 检测到了基线 ctDNA 水平。切除后 4 周可检测到 ctDNA 水平的患者的 PFS 较差（风险比 [HR]，34.0；95% CI，2.6-4758.6；磷= .006）和 OS（HR，11.7；95% CI，1.5-129.9；磷= .02) 与那些无法检测到的水平相比。 K17 高表达的患者的 PFS 较差（HR，2.7；95% CI，0.7-10.9；磷= .09）和 OS（HR，3.2；95% CI，0.8-13.6；磷= .07)。结论和相关性这项非随机对照试验达到了其主要终点，围手术期 mFOLFIRINOX 值得在随机临床试验中进行进一步评估。术后 ctDNA 阳性与复发密切相关。 K17 和 ctDNA 是有前途的生物标志物，需要在未来的前瞻性研究中进行额外验证。试验注册临床试验。政府标识符： NCT02047474