Efficacy of Perioperative Chemotherapy for Resectable Pancreatic Adenocarcinoma A Phase 2 Randomized Clinical Trial
Efficacy of Perioperative Chemotherapy for Resectable Pancreatic Adenocarcinoma A Phase 2 Randomized Clinical Trial
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DOI：
10.1001/jamaoncol.2020.7328
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发表时间：
2021-01-21
期刊：
影响因子：
28.4
通讯作者：
Hochster, Howard S.
中科院分区：
文献类型：
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作者：
Sohal, Davendra P. S.;Duong, Mai;Hochster, Howard S.
重要：可切除胰腺导管腺癌(PDA)根治性治疗后的临床结果仍不理想。为了评估围手术期多药剂化疗早期控制全身疾病的可能性，我们进行了一项前瞻性试验。目的确定围手术期化疗对可切除PDA的两年总存活率。设计、设置和参与者这是一项围术期化疗的随机2期试验，采用挑选赢家的设计。这项研究是在全国临床试验网络上进行的，包括美国各地的学术和社区中心。符合资格要求的患者Zubrod功能评分为0或1，确认为PDA的组织诊断，并根据组间标准可切除疾病。干预围术期(术前12周，术后12周)使用氟尿嘧啶、伊立替康和奥沙利铂(mFOLFIRINOX，ARM 1)或吉西他滨/NAB-紫杉醇(ARM 2)进行化疗。主要结果和衡量主要结果是：采用挑选者设计，主要结果是2年总生存期(OS)；对于100名符合条件的患者，计划累积至多150名患者，以解决2015年至2018年中心放射学审查认为不合格的患者。在中心放射学复查中，43名患者(29%)有超过可切除标准的不符合条件的疾病。合格和可评价患者102例，第1组55例，第2组47例，年龄中位数(范围)分别为66岁(44~76岁)和(46~76岁)，男性36例(65%)，第2组24例(51%)。第1组Zubrod评分0分34例(62%)，第2组31例(66%)；第1组44例(80%)，第2组39例(83%)。在102名患者中，84%和85%完成了术前化疗，73%和70%接受了切除，49%和40%完成了所有治疗。不良反应包括血液毒性、疲劳感和胃肠道毒性。ARM 1和ARM 2的2年OS分别为47%(95%CI，31%~61%)和48%(95%CI，31%~63%)，中位OS分别为23.2个月(95%CI，17.6~45.9个月)和23.6个月(95%CI，17.8~31.7个月)。ARM对两年运营状况的估计都没有明显高于40%的先验门槛。切除后的中位无瘤存活期，第1组为10.9个月，第2组为14.2个月。结论和相关性：与可切除胰腺癌辅助试验的历史数据相比，这项第2阶段随机临床试验没有显示围手术期化疗的OS改善。对于所有开始接受可切除PDA治疗的符合条件的患者，mFOLFIRINOX和吉西他滨/NAB-紫杉醇的两年OS分别为47%和48%。该试验还证明了围手术期化疗的足够安全性和高切除率，以及可切除性标准的质量控制方面的挑战。
IMPORTANCE Clinical outcomes after curative treatment of resectable pancreatic ductal adenocarcinoma (PDA) remain suboptimal. To assess the potential of early control of systemic disease with multiagent perioperative chemotherapy, we conducted a prospective trial.OBJECTIVE To determine 2-year overall survival (OS) using perioperative chemotherapy for resectable PDA.DESIGN, SETTING, AND PARTICIPANTS This was a randomized phase 2 trial of perioperative chemotherapy with a pick-the-winner design. It was conducted across the National Clinical Trials Network, including academic and community centers all across the US. Eligibility required patients with Zubrod Performance Score of 0 or 1, confirmed tissue diagnosis of PDA, and resectable disease per Intergroup criteria.INTERVENTIONS Perioperative (12 weeks preoperative, 12 weeks postoperative) chemotherapy with either fluorouracil, irinotecan, and oxaliplatin (mFOLFIRINOX, arm 1) or gemcitabine/nab-paclitaxel (arm 2).MAIN OUTCOMES AND MEASURES The primary outcome was 2-year overall survival (OS), using a pick-the-winner design; for 100 eligible patients, accrual up to 150 patients was planned to account for cases deemed ineligible at central radiology review.RESULTS From 2015 to 2018, 147 patients were enrolled; 43 patients (29%) had ineligible disease, beyond resectability criteria, at central radiology review. There were 102 eligible and evaluable patients, 55 in arm 1 and 47 in arm 2, of whom the median (range) age was 66 (44-76) and 64 (46-76) years, respectively; 36 patients (65%) in arm 1 and 24 (51%) in arm 2 were men. In arm 1, 34 (62%) had Zubrod Performance Score of 0, while in arm 2, 31 (66%) did; and 44 (80%) in arm 1 and 39 (83%) in arm 2 had head tumors. Of 102 patients, 84% and 85% completed preoperative chemotherapy, 73% and 70% underwent resection, and 49% and 40% completed all treatment. Adverse events were expected hematologic toxic effects, fatigue, and gastrointestinal toxicities. Two-year OS was 47% (95% CI, 31%-61%) for arm 1 and 48% (95% CI, 31%-63%) for arm 2; median OS was 23.2 months (95% CI, 17.6-45.9 months) and 23.6 months (95% CI, 17.8-31.7 months). Neither arm's 2-year OS estimate was significantly higher than the a priori threshold of 40%. Median disease-free survival after resection was 10.9 months in arm 1 and 14.2 months in arm 2.CONCLUSIONS AND RELEVANCE This phase 2 randomized clinical trial did not demonstrate an improved OS with perioperative chemotherapy, compared with historical data from adjuvant trials in resectable pancreatic cancer. Two-year OS was 47% with mFOLFIRINOX and 48% with gemcitabine/nab-paclitaxel for all eligible patients starting treatment for resectable PDA. The trial also demonstrated adequate safety and high resectability rates with perioperative chemotherapy, and challenges in quality control for resectability criteria.