Neoadjuvant FOLFIRINOX versus neoadjuvant gemcitabine-based chemoradiotherapy in resectable and borderline resectable pancreatic cancer (PREOPANC-2): a multicentre, open-label, phase 3 randomised trial.

Methods

In this investigator-initiated, open-label, nationwide, phase 3 randomised trial, patients aged 18 years or older with resectable or borderline resectable PDAC and a WHO performance status of 0 or 1 were enrolled across 19 Dutch centres.

在这项由研究者发起的、开放标签的、全国性的、III期随机试验中，年龄在18岁或以上的、具有可切除或边缘可切除PDAC和WHO体能状态评分为0或1的患者，在19个荷兰中心进行了招募。

Patients in the FOLFIRINOX (FFX) group received FOLFIRINOX (85 mg/m2 intravenous oxaliplatin, 180 mg/m2 intravenous irinotecan, 400 mg/m2 intravenous leucovorin, followed by a 400 mg/m2 intravenous fluorouracil bolus and then continuous infusion at 2400 mg/m2 intravenously over 46 h every 14 days for eight cycles) followed by surgery without adjuvant treatment.

FOLFIRINOX (FFX)组的患者接受了FOLFIRINOX治疗（静脉注射奥沙利铂85 mg/m2，静脉注射伊立替康180 mg/m2，静脉注射亚叶酸钙400 mg/m2，随后静脉注射氟尿嘧啶400 mg/m2冲击剂量，然后以2400 mg/m2的剂量持续静脉输注46小时，每14天一次，共八个周期），之后进行手术，不接受辅助治疗。

Patients in the chemoradiotherapy (CRT) group received three cycles of neoadjuvant gemcitabine (1000 mg/m2 intravenously on days 1, 8, and 15 of each 28-day cycle and on days 1 and 8 only for cycles one and three) combined with hypofractionated radiotherapy (36 Gy in 15 fractions) during the second cycle only, followed by surgery and four cycles of adjuvant gemcitabine.

化疗放疗(CRT)组的患者接受了三周期的新辅助吉西他滨治疗（每个28天周期的第1、8、15天静脉注射吉西他滨1000 mg/m2，对于第一和第三周期，仅在第1和第8天进行静脉注射），在第二周期期间仅接受低分割放疗（36 Gy分15次照射），随后进行手术和四周期的辅助吉西他滨治疗。

Randomisation (1:1) was done using a minimisation technique and stratified by resectability status (resectable vs borderline resectable disease) and centre.

随机分配（1:1）使用最小化技术进行，并根据可切除性状态（可切除性 vs 边缘可切除性病变）和中心进行分层。

The primary endpoint was overall survivalin the modified intention-to-treatpopulation, after excluding ineligible patients.

主要终点是在排除不合格患者后，修改意向治疗人群中总生存期。

Data on race and ethnicity were not collected.

未收集种族和民族数据。

This trial is registered with EudraCT (2017-002036-17) and is complete.

该试验已在EudraCT（2017-002036-17）注册，并已完成。

Results

From June 5, 2018, to Jan 28, 2021, 375 patients were randomly assigned to the FFX group (n=188) or the CRT group (n=187).

2018年6月5日至2021年1月28日，375名患者被随机分配到FFX组（n=188）或CRT组（n=187）。

Six patients (three per group) were excluded due to ineligibility (n=4) or immediate withdrawal of informed consent after randomisation (n=2). 208 (56%) of 369 patients were male and 161 (44%) were female.

由于不符合入选标准（n=4）或随机化后立即撤回知情同意（n=2），每组各有三名患者被排除在外。在369名患者中，208名（56%）为男性，161名（44%）为女性。

After a median follow-up of 42·3 months (IQR 35·7-48·7), median overall survivalwas 21·9 months (95% CI 17·7-27·0) in the FFX group versus 21·3 months (16·8-25·5) in the CRT group (HR 0·88 [95% CI 0·69-1·13], p=0·32).

中位随访时间为42.3个月（四分位数间距35.7-48.7），FFX组的中位总生存期为21.9个月（95%置信区间17.7-27.0），而CRT组为21.3个月（95%置信区间16.8-25.5）（HR 0.88 [95%置信区间0.69-1.13]，p=0.32）。

The most common grade 3-4 adverse events were neutropenia (43 [25%] of 175 in the FFX group vs 38 [22%] of 176 in the CRT group), diarrhoea (41 [23%] vs two [1%]), and leukopenia (14 [8%] vs 26 [15%]).

最常见的3-4级不良事件是中性粒细胞减少症（FFX组175人中有43人[25%]，CRT组176人中有38人[22%]）、腹泻（FFX组41人[23%]，CRT组2人[1%]）和白细胞减少症（FFX组14人[8%]，CRT组26人[15%]）。

Serious adverse events occurred in 85 (49%) patients in the FFX group compared with 75 (43%) in the CRT group (p=0·26).

FFX组中有85名（49%）患者发生了严重不良事件，而CRT组中有75名（43%）患者发生了严重不良事件（p=0.26）。

Adverse events of grades 3 or worse occurred in 117 (67%) patients in the FFX group versus 106 (60%) patients in the CRT group (p=0·20).

FFX组中有117名（67%）患者发生了3级或更严重的不良事件，而CRT组中有106名（60%）患者发生了3级或更严重的不良事件（p=0.20）。

Treatment-related deaths occurred in two (1%) patients in the FFX group (multi-organ failure and intestinal mucositis) and one (1%) patient in the CRT group (upper gastrointestinal haemorrhage).

治疗相关死亡发生在FFX组的两名（1%）患者中（多器官衰竭和肠粘膜炎）以及CRT组的一名（1%）患者中（上消化道出血）。

interpretation

This randomised trial did not show a difference in overall survivalbetween neoadjuvant FOLFIRINOX and neoadjuvant gemcitabine-based chemoradiotherapy in patients with resectable or borderline resectable PDAC.

这项随机试验没有显示出新辅助FOLFIRINOX与新辅助基于吉西他滨的放化疗在可切除或边缘可切除PDAC患者总生存上的差异。

Both neoadjuvant treatment regimens may be considered in these patients.

这两种新辅助治疗方案都可以考虑用于这些患者。

funding

Dutch Cancer Society and ZonMw.

荷兰癌症协会和ZonMw。