Abstract
BackgroundNeoadjuvant therapy has several potential advantages over upfront surgery in patients with localized pancreatic cancer; more patients receive systemic treatment, fewer patients undergo futile surgery, and R0 resection rates are higher, thereby possibly improving overall survival (OS). Two recent randomized trials have suggested benefit of neoadjuvant chemoradiotherapy over upfront surgery, both including single-agent chemotherapy regimens. Potentially, the multi-agent FOLFIRINOX regimen (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) may further improve outcomes in the neoadjuvant setting for localized pancreatic cancer, but randomized studies are needed. The PREOPANC-2 trial investigates whether neoadjuvant FOLFIRINOX improves OS compared with neoadjuvant gemcitabine-based chemoradiotherapy and adjuvant gemcitabine in resectable and borderline resectable pancreatic cancer patients.MethodsThis nationwide multicenter phase III randomized controlled trial includes patients with pathologically confirmed resectable and borderline resectable pancreatic cancer with a WHO performance score of 0 or 1. Resectable pancreatic cancer is defined as no arterial and ≤ 90 degrees venous involvement; borderline resectable pancreatic cancer is defined as ≤90 degrees arterial and ≤ 270 degrees venous involvement without occlusion. Patients receive 8 cycles of neoadjuvant FOLFIRINOX chemotherapy followed by surgery without adjuvant treatment (arm A), or 3 cycles of neoadjuvant gemcitabine with hypofractionated radiotherapy (36 Gy in 15 fractions) during the second cycle, followed by surgery and 4 cycles of adjuvant gemcitabine (arm B). The primary endpoint is OS by intention-to-treat. Secondary endpoints include progression-free survival, quality of life, resection rate, and R0 resection rate. To detect a hazard ratio of 0.70 with 80% power, 252 events are needed. The number of events is expected to be reached after inclusion of 368 eligible patients assuming an accrual period of 3 years and 1.5 years follow-up.DiscussionThe PREOPANC-2 trial directly compares two neoadjuvant regimens for patients with resectable and borderline resectable pancreatic cancer. Our study will provide evidence on the neoadjuvant treatment of choice for patients with resectable and borderline resectable pancreatic cancer.Trial registrationPrimary registry and trial identifying number: EudraCT: 2017–002036-17.Date of registration: March 6, 2018.Secondary identifying numbers: The Netherlands National Trial Register – NL7094, NL61961.078.17, MEC-2018-004.
Highlights
Pancreatic ductal adenocarcinoma is often diagnosed at an advanced stage
Eligible patients are randomly assigned to either receive neoadjuvant FOLFIRINOX followed by surgery without adjuvant treatment or neoadjuvant gemcitabine-based chemoradiotherapy followed by surgery and adjuvant gemcitabine (Fig. 1)
Discussion we describe the protocol of the PREOPANC-2 trial, a multicenter randomized phase III trial conducted by the Dutch Pancreatic Cancer Group in the Netherlands, which was designed to compare the efficacy of two neoadjuvant treatment strategies for patients with resectable and borderline resectable pancreatic cancer
Summary
Design The PREOPANC-2 trial is a multicenter randomized phase III superiority trial, initiated by the Dutch Pancreatic Cancer Group (DPCG). Radiologic response is defined according to RECI ST criteria version 1.1 comparing pre-randomization and restaging imaging after 4 and 8 cycles of FOLFIRINOX (arm A) or after chemoradiotherapy (arm B). These time points are used to assess tumor marker response. In order to detect a hazard ratio (HR) of 0.70 with 80% power (2-sided significance level alpha = 0.05), a total of 252 events (deaths) need to be observed This HR translates into a median OS of about 24 months in the intervention arm, which is consistent with a large patient-level meta-analysis on neoadjuvant FOLFIRINOX treatment for borderline resectable pancreatic cancer [16]. Prespecified subgroup analyses include: patients that received at least one cycle of neoadjuvant treatment, patients that underwent a resection, patients that underwent an R0 resection, patients that completed all scheduled treatment, for the subgroups resectable and borderline resectable pancreatic cancer, patients younger vs. older than 65 years, patients with high and low CA 19–9, and patients with performance score 0 vs. 1
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