Pancreas
Lancet Gastroenterol Hepatol. 2024;9(3):205–17
Neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer (NORPACT-1): A multicenter, randomized, phase 2 trial
Background: In patients undergoing resection for pancreatic cancer, adjuvant modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) improves overall survival (OS) compared with alternative chemotherapy regimens. The authors aimed to compare the efficacy and safety of neoadjuvant FOLFIRINOX with the standard strategy of upfront surgery in patients with resectable pancreatic ductal adenocarcinoma (PDAC).
Methods: NORPACT-1 was a multicenter, randomized, phase 2 trial done in 12 hospitals in Denmark, Finland, Norway, and Sweden. Eligible patients were aged 18 years or older, with a WHO performance status of 0 or 1, and had a resectable tumor of the pancreatic head radiologically strongly suspected to be pancreatic adenocarcinoma. Participants were randomly assigned (3:2 before October, 2018, and 1:1 after) to the neoadjuvant FOLFIRINOX group or upfront surgery group. Patients in the neoadjuvant FOLFIRINOX group received 4 neoadjuvant cycles of FOLFIRINOX (oxaliplatin 85 mg/m², irinotecan 180 mg/m², leucovorin 400 mg/m², and fluorouracil 400 mg/m² bolus then 2400 mg/m² over 46 hours on day 1 of each 14-day cycle), followed by surgery and adjuvant chemotherapy. Patients in the upfront surgery group underwent surgery and then received adjuvant chemotherapy. Initially, adjuvant chemotherapy was gemcitabine plus capecitabine (gemcitabine 1000 mg/m² over 30 minutes on days 1, 8, and 15 of each 28-day cycle and capecitabine 830 mg/m² twice daily for 3 weeks with 1 week of rest in each 28-day cycle; 4 cycles in the neoadjuvant FOLFIRINOX group, 6 cycles in the upfront surgery group). A protocol amendment was subsequently made to permit use of adjuvant modified FOLFIRINOX (oxaliplatin 85 mg/m², irinotecan 150 mg/m², leucovorin 400 mg/m², and fluorouracil 2400 mg/m² over 46 hours on day 1 of each 14-day cycle; 8 cycles in the neoadjuvant FOLFIRINOX group, 12 cycles in the upfront surgery group). Randomization was performed with a computerized algorithm that stratified for each participating center and used a concealed block size of 2–6. Patients, investigators, and study team members were not masked to treatment allocation. The primary end point was OS at 18 months. Analyses were done in the intention-to-treat (ITT) and per-protocol (PP) populations. Safety was assessed in all patients who were randomly assigned and received at least 1 cycle of neoadjuvant or adjuvant therapy.
Findings: Between February 8, 2017, and April 21, 2021, 77 patients were randomly assigned to receive neoadjuvant FOLFIRINOX and 63 to undergo upfront surgery. All patients were included in the ITT analysis. For the PP analysis, 17 patients (22%) were excluded from the neoadjuvant FOLFIRINOX group (10 did not receive neoadjuvant therapy, 4 did not have PDAC, and 3 received another neoadjuvant regimen), and 8 (13%) were excluded from the upfront surgery group (7 did not have PDAC and 1 did not undergo surgical exploration). 61 of 77 patients (79%) in the neoadjuvant FOLFIRINOX group received neoadjuvant therapy. The proportion of patients alive at 18 months by ITT was 60% (95% confidence interval [CI]: 49–71) in the neoadjuvant FOLFIRINOX group versus 73% (95% CI: 62–84) in the upfront surgery group (p = 0·032), and median OS by ITT was 25.1 months (95% CI: 17.2–34.9) versus 38.5 months (95% CI: 27.6–not reached; hazard ratio [HR] = 1.52 [95% CI: 1.00–2.33], log-rank p = 0.050). The proportion of patients alive at 18 months in PP analysis was 57% (95% CI: 46–67) in the neoadjuvant FOLFIRINOX group versus 70% (95% CI: 55–83) in the upfront surgery group (p = 0.14), and median OS in PP population was 23.0 months (95% CI: 16.2–34.9) versus 34.4 months (95% CI: 19.4–not reached; HR = 1.46 [95% CI: 0.99–2.17], log-rank p = 0.058). In the safety population, 42 of 73 patients (58%) in the neoadjuvant FOLFIRINOX group and 19 of 47 patients (40%) in the upfront surgery group had at least 1 grade 3 or worse adverse event. 63 of 77 patients (82%) in the neoadjuvant group and 56 of 63 patients (89%) in the upfront surgery group had resection (p = 0.24). One sudden death of unknown cause and 1 COVID-19-related death occurred after the first cycle of neoadjuvant FOLFIRINOX. Adjuvant chemotherapy was initiated in 51 of 59 patients (86%) with resected PDAC in the neoadjuvant FOLFIRINOX group and 44 of 49 patients (90%) with resected PDAC in the upfront surgery group (p = 0.56). Adjuvant modified FOLFIRINOX was given to 13 patients (25%) in the neoadjuvant FOLFIRINOX group and 19 patients (43%) in the upfront surgery group. During adjuvant chemotherapy, neutropenia (11 patients [22%] in the neoadjuvant FOLFIRINOX group and 5 [11%] in the upfront surgery group) was the most common grade 3 or worse adverse event.
Interpretation: This phase 2 trial did not show a survival benefit from neoadjuvant FOLFIRINOX in resectable pancreatic ductal adenocarcinoma (PDAC) compared with upfront surgery. Implementation of neoadjuvant FOLFIRINOX was challenging. Future trials on treatment sequencing in resectable PDAC should be biomarker driven.