Phase II randomized Nordic multicenter trial | 12 centers | n = 140 | Resectable PDAC | Lancet Gastroenterology & Hepatology 2024 **Labori et al.** Knut Joar Labori Published in The Lancet Gastroenterology & Hepatology, 2024 Enrollment: 2017–2021 [PubMed Link](https://pubmed.ncbi.nlm.nih.gov/38237621/) --- ### Essential Takeaway NORPACT-1 did not demonstrate a survival advantage for perioperative neoadjuvant FOLFIRINOX in resectable PDAC despite improved nodal sterilization and margin outcomes. The trial challenged universal adoption of neoadjuvant therapy in clearly resectable disease and reinforced continued selective use based on biologic risk factors rather than anatomy alone. --- ### Clinical Question In resectable pancreatic ductal adenocarcinoma (PDAC), does perioperative neoadjuvant FOLFIRINOX improve survival compared with upfront surgery followed by adjuvant chemotherapy? --- ### Population - Resectable PDAC - Primarily pancreatic head cancers - Treated at high-volume Nordic centers --- ### Study Design #### Arm 1 — Perioperative FOLFIRINOX - 4 cycles neoadjuvant FOLFIRINOX - Restaging - Surgery - 8 cycles adjuvant FOLFIRINOX #### Arm 2 — Upfront Surgery - Immediate surgery - 12 cycles adjuvant FOLFIRINOX > Adjuvant gemcitabine-based regimens were initially permitted but the protocol was amended following publication of PRODIGE-24. --- ### Endpoints #### Primary Endpoint 18-month overall survival (OS) #### Secondary Endpoints - Progression-free survival (PFS) - Median OS - OS after resection - Per-protocol OS - Pathologic response - Nodal positivity - Margin status - 90-day morbidity/mortality - Quality of life --- ### Key Results ### Primary Endpoint 18-month OS favored upfront surgery: - Neoadjuvant arm: - 60% - Upfront surgery arm: - 73% - p = 0.032 --- ### Median Overall Survival - Neoadjuvant: - 25.1 months - Upfront surgery: - 38.5 months --- ### Pathologic Outcomes Neoadjuvant therapy improved several local and pathologic metrics. #### Node Positive Disease - 71% vs 86% - p < 0.0001 #### R1 Resection Rate (R1 defined as viable tumor within 1 mm) - 44% vs 61% - p = 0.018 --- ### Additional Findings #### Improved Local Metrics Without OS Benefit Although neoadjuvant therapy improved: - nodal sterilization - margin status - pathologic downstaging these surrogate improvements did not translate into improved overall survival. #### Treatment Attrition A meaningful proportion of patients in the neoadjuvant arm never ultimately reached surgery, highlighting challenges of prolonged perioperative therapy in resectable disease. --- ### Interpretation NORPACT-1 became one of the most important modern trials challenging universal neoadjuvant therapy in clearly resectable PDAC. The study suggested that benefits observed in borderline resectable disease may not automatically translate to anatomically resectable tumors. The trial also reinforced a central principle in pancreatic oncology: > improved local or pathologic outcomes do not necessarily produce survival benefit. Its findings tempered enthusiasm for routine neoadjuvant therapy in all resectable patients and strengthened arguments for biologically selective approaches. --- ### Important Limitations #### Phase II Design - Not definitive phase III evidence #### Limited Power - Relatively small sample size #### Treatment Delivery Challenges - Significant attrition in the neoadjuvant arm - Some patients never reached surgery #### Per-Protocol vs ITT Complexity - Per-protocol analyses differed from ITT findings - Interpretation remains controversial #### Applicability Findings apply specifically to: - clearly resectable PDAC - Nordic high-volume center practice patterns - perioperative FOLFIRINOX strategies --- ### Practice Impact NORPACT-1 tempered enthusiasm for universal neoadjuvant therapy in resectable PDAC. Many centers continue to favor upfront surgery for clearly resectable disease while reserving neoadjuvant therapy for biologically higher-risk tumors, including: - elevated CA19-9 - suspicious regional nodes - large primary tumors - equivocal vascular involvement - concerning biologic behavior The trial reinforced movement toward biology-driven rather than anatomy-only treatment selection.