Total neoadjuvant FOLFIRINOX versus neoadjuvant gemcitabine-based chemoradiotherapy and adjuvant gemcitabine for resectable and borderline resectable pancreatic cancer (PREOPANC-2 trial): study protocol for a nationwide multicenter randomized controlled trial

Abstract

Background Neoadjuvant 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. Methods This 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. Discussion The 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 registration Primary 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.

Added Value of Radiotherapy Following Neoadjuvant FOLFIRINOX for Resectable and Borderline Resectable Pancreatic Cancer: A Systematic Review and Meta-Analysis

“…56 Finally, the Dutch PREOPANC-2 trial has completed accrual of 368 (B)RPC patients who were randomized to total neoadjuvant FOLFIRINOX (8 cycles) or neoadjuvant gemcitabine-based chemoradiotherapy and adjuvant gemcitabine, with results expected in 2022. 57 Some limitations should be taken into account when interpreting the results of our study. First, no randomized trial was included that directly compared FOLFIRINOX with or without radiotherapy.…”

“…48,54 Four ongoing randomized controlled trials may provide better insights in the individual contributions of systemic chemotherapy and radiotherapy for BRPC patients. [55][56][57] In the ALLIANCE trial A021501, 134 BRPC patients are randomized to neoadjuvant mFOLFIRINOX (8 cycles) or neoadjuvant mFOLFIRINOX (7 cycles) plus SBRT, with surgery and adjuvant FOLFOX in both arms. 55 In the French PANDAS-PRODIGE 44 trial (NCT02676349), 90 BRPC patients are randomized to neoadjuvant mFOL-FIRINOX (8 cycles) or neoadjuvant mFOLFIRINOX (8 cycles) with subsequent capecitabine-based chemoradiotherapy, followed by surgery and adjuvant gemcitabine or 5-FU in both arms.…”

Neoadjuvant therapy for pancreatic cancer

“…However, there are several limitations to this trial, especially regarding the regiments used: as highlighted before, multi-drug regimens have shown to be the most effective in pancreatic cancer, while in the PREOPANC trial gemcitabine-based monotherapies where used. The study protocol for PREOPANC-2 trial has been recently published, comparing neoadjuvant FOLFIRINOX to neoadjuvant gemcitabine and adjuvant gemcitabine [ 44 ].…”

Neoadjuvant therapy in resectable pancreatic cancer—is this the way forward?—a narrative review

“…The MD Anderson large retrospective series found no significant differences between FOLFIRINOX and gemcitabine + nab-paclitaxel in terms of overall survival for all stage of disease, despite more favorable response and resection rates after FOLFIRINOX (28). PREOPANC-2 (to be completed within 2022) is designed to identify the best preoperative treatment for resectable and borderline resectable PDAC, randomizing patients to either receive preoperative FOLFIRINOX (eight cycles) alone or preoperative gemcitabine-based chemo-radiotherapy (three cycles) and subsequent adjuvant treatment (34). The recent SWOG S1505 was the first trial to enroll exclusively patients with resectable PDAC (35).…”