Phase III | Dutch multicenter randomized trial | n=246 | Resectable + BR-PDAC | JCO 2020 **Versteijne et al.** Published in Journal of Clinical Oncology, 2020 Enrollment: 2013–2017 [PubMed Link](https://pubmed.ncbi.nlm.nih.gov/32105518/) Long-term follow-up published 2022: [PubMed Link](https://pubmed.ncbi.nlm.nih.gov/35084987/) --- ### Essential Takeaway PREOPANC-1 demonstrated **improved R0 resection, disease-free survival, and locoregional control** with **neoadjuvant gemcitabine-based chemoradiotherapy** versus upfront surgery in resectable and borderline resectable PDAC. Long-term follow-up later demonstrated an overall survival benefit, with the strongest signal observed in borderline resectable disease. The trial became foundational support for modern neoadjuvant-first paradigms in pancreatic cancer. --- ### Clinical Question Does neoadjuvant gemcitabine-based chemoradiotherapy improve outcomes compared with upfront surgery in resectable and borderline resectable PDAC? --- ### Population - Resectable PDAC - Borderline resectable PDAC Importantly, this trial included both groups, which significantly influenced interpretation of subgroup outcomes. --- ### Study Design #### Arm 1 — Neoadjuvant Chemoradiotherapy - Staging laparoscopy - 3 cycles gemcitabine - Hypofractionated chemoradiation during cycle 2 - Restaging - Surgery - 4 additional cycles adjuvant gemcitabine #### Arm 2 — Upfront Surgery - Immediate surgery - 6 cycles adjuvant gemcitabine --- ### Endpoints #### Primary Endpoint Overall survival (OS) #### Secondary Endpoints - Disease-free survival (DFS) - Resection rate - R0 resection rate - Distant metastases - Locoregional failure - Toxicity --- ### Key Results (JCO 2020) #### Overall Survival - 16.0 vs 14.3 months - HR 0.78 - p = 0.096 Although technically negative, the hazard ratio favored neoadjuvant treatment. --- ### R0 Resection - 71% vs 40% - p < 0.001 Most pronounced in BR-PDAC: - 79% vs 13% - OR 24.2 - p < 0.001 --- ### Disease-Free Survival - 8.1 vs 7.7 months - p = 0.032 --- ### Locoregional Failure-Free Interval - Not reached vs 13.4 months - HR 0.56 - p = 0.003 --- ### Protocol Adherence Analysis Among patients with “perfect” protocol adherence: - Median OS: - 35.2 vs 19.8 months This exploratory finding substantially increased enthusiasm for neoadjuvant strategies despite the formally negative primary endpoint. --- ### Long-Term Follow-Up (2022) ### Overall Survival #### 5-Year OS - 20.5% vs 6.5% #### Median OS - 15.7 vs 14.3 months - HR 0.73 - p = 0.025 With longer follow-up, survival curves separated further over time. --- ### Additional Findings Neoadjuvant therapy continued to demonstrate: - improved local control - higher R0 resection rates - improved pathologic outcomes Benefit remained most pronounced in borderline resectable disease. --- ### Interpretation PREOPANC became one of the foundational trials supporting neoadjuvant therapy in pancreatic cancer, particularly for borderline resectable disease. Although the initial publication was technically negative for OS, the overall dataset demonstrated: - improved margin-negative resection - improved local control - improved DFS - favorable long-term survival trends The trial also highlighted limitations of surgery-first paradigms in biologically aggressive disease. --- ### Important Limitations #### Older Chemotherapy Backbone - Gemcitabine-based regimen - Predates widespread mFOLFIRINOX use #### Mixed Population - Combined resectable + borderline cohorts complicate interpretation #### Initial Negative Trial - Primary endpoint narrowly missed significance initially - Interpretation evolved after long-term follow-up #### Applicability to Modern Practice Modern practice increasingly favors: - mFOLFIRINOX-based regimens - selective RT rather than gemcitabine-based chemoradiotherapy alone. --- ### Practice Impact PREOPANC substantially accelerated acceptance of: - neoadjuvant therapy for BR-PDAC - systemic-first treatment paradigms - biologic selection before surgery It remains one of the most frequently cited trials supporting neoadjuvant treatment in pancreatic cancer.