Phase III Dutch multicenter randomized trial | n = 375 | Resectable + BR-PDAC | Lancet Oncology 2025 **Janssen et al.** Quinty P. Janssen Published in The Lancet Oncology, 2025 Enrollment: 2018–2021 [PubMed Link](https://pubmed.ncbi.nlm.nih.gov/40945523/) --- ### Essential Takeaway PREOPANC-2 failed to demonstrate superiority of total neoadjuvant mFOLFIRINOX over gemcitabine-based chemoradiotherapy in resectable and borderline resectable PDAC. The trial reinforced that multiple neoadjuvant strategies remain viable and highlighted ongoing uncertainty regarding the optimal balance between systemic intensification and radiation-based local control. --- ### Clinical Question In resectable and borderline resectable PDAC, is total neoadjuvant mFOLFIRINOX superior to neoadjuvant gemcitabine-based chemoradiotherapy? --- ### Population - Resectable PDAC - Borderline resectable PDAC Importantly, this trial compared two neoadjuvant strategies rather than neoadjuvant therapy versus upfront surgery. --- ### Study Design #### Arm 1 — Total Neoadjuvant FOLFIRINOX - 8 cycles neoadjuvant mFOLFIRINOX - Restaging after cycle 4 - Restaging after cycle 8 - Surgery #### Arm 2 — Gemcitabine-Based Chemoradiotherapy - 3 cycles gemcitabine - Hypofractionated RT during cycle 2 - Restaging - Surgery - 4 cycles adjuvant gemcitabine --- ### Endpoints #### Primary Endpoint Overall survival (OS) Defined as death from any cause after randomization. #### Secondary Endpoints - Progression-free survival (PFS) - Disease-free survival (DFS) - Locoregional failure - Distant metastasis-free interval - Histopathologic response - CA19-9 response - Treatment completion rates - Dose reductions - Toxicity/adverse events --- ### Key Results #### Overall Survival #### Entire Cohort - 1-year OS: - 76% vs 70% - 3-year OS: - 36% vs 33% No statistically significant OS difference between strategies. --- ### Resectable Disease Subgroup - Median OS: - 21.5 months (FOLFIRINOX) - 22.5 months (CRT) - p = 0.64 No survival benefit observed with FOLFIRINOX. --- ### Borderline Resectable Subgroup - Median OS: - 23.4 months (FOLFIRINOX) - 17.0 months (CRT) - p = 0.30 Numerically favored FOLFIRINOX, though not statistically significant. --- ### Pathologic Findings #### Node Positive Disease Higher pN+ rates were observed in the FOLFIRINOX group: - p = 0.0073 This finding was somewhat unexpected given the intensity of systemic therapy. --- ### Toxicity Despite substantially more cytotoxic therapy: - adverse event rates were similar between groups These findings supported feasibility of prolonged neoadjuvant FOLFIRINOX in appropriately selected patients. --- ### Additional Findings #### No Dominant Neoadjuvant Strategy Emerged The trial demonstrated that: - systemic intensification with FOLFIRINOX - radiation-focused neoadjuvant strategies can both produce comparable outcomes in PDAC. #### Borderline Resectable Signal Although statistically nonsignificant, the BR-PDAC subgroup numerically favored FOLFIRINOX, suggesting certain higher-risk patients may derive greater benefit from intensified systemic therapy. --- ### Interpretation PREOPANC-2 became an important modern neoadjuvant PDAC trial because it directly compared two competing neoadjuvant philosophies: - systemic intensification with prolonged FOLFIRINOX - combined modality chemoradiotherapy The study reinforced that neoadjuvant therapy is now central in PDAC management but suggested no universally dominant regimen has yet emerged. It also highlighted continued uncertainty regarding the precise role of radiation in modern pancreatic cancer treatment algorithms. --- ### Important Limitations #### Not Powered for Subgroup Conclusions - BR-PDAC subgroup differences may still be clinically meaningful despite statistical nonsignificance #### Cross-Trial Comparisons Are Difficult Results cannot be directly compared with: - PREOPANC-1 - ALLIANCE A021501 - NORPACT-1 due to differing populations, treatment schemas, and trial designs. #### Evolving Treatment Standards - RT techniques - supportive care - surgical selection - systemic regimens continue to evolve rapidly. #### Unexpected Node Positivity Finding Higher pN+ rates in the FOLFIRINOX arm remain difficult to fully interpret and may reflect: - biologic selection - treatment timing - surgical/pathologic variability --- ### Practice Impact PREOPANC-2 reinforced that: - neoadjuvant therapy is now foundational in PDAC management - multiple neoadjuvant strategies remain reasonable - institutional philosophy continues to influence: - RT utilization - chemotherapy duration - total neoadjuvant approaches The trial also supported feasibility and tolerability of prolonged neoadjuvant FOLFIRINOX in appropriately selected patients.