Background
Phase III RCT (PREOPANC). 246 patients with resectable or borderline resectable pancreatic cancer at 16 Dutch centers. Randomized 1:1 to preoperative gemcitabine-based chemoradiotherapy followed by surgery and adjuvant gemcitabine, versus upfront surgery and adjuvant gemcitabine.
Interventions and follow up
Arm A: Gemcitabine 1,000 mg/m² days 1, 8 for 3 cycles → gemcitabine-based CRT (36 Gy in 15 fx + gemcitabine) → surgery → 4 cycles adjuvant gemcitabine
Arm B: Upfront surgery → 6 cycles adjuvant gemcitabine
Primary endpoint: Overall survival
mFollow up: 27 month
Arm B: Upfront surgery → 6 cycles adjuvant gemcitabine
Primary endpoint: Overall survival
mFollow up: 27 month
Results
mOS (ITT): 16.0 months (preoperative) vs 14.3 months (upfront surgery), HR 0.78, P=.047
R0 resection (of all resected): 71% vs 40%, P<.001
Pathologic complete response: 10% in preoperative arm
Resection rate: 61% vs 72% (lower in preoperative arm due to progression)
R0 resection (of all resected): 71% vs 40%, P<.001
Pathologic complete response: 10% in preoperative arm
Resection rate: 61% vs 72% (lower in preoperative arm due to progression)
Adverse events
Main adverse events: Grade ≥3 preoperative therapy toxicity: 52% in experimental arm. Grade ≥3 postoperative complications comparable. 30-day postoperative mortality: 3% vs 4%.
Conclusions
Preoperative gemcitabine-based CRT significantly improved OS (HR 0.78, P=.047) and dramatically improved R0 resection rates (71% vs 40%) compared to upfront surgery in resectable/borderline resectable pancreatic cancer. This provides phase III evidence supporting neoadjuvant therapy in BRPC.
Key Limitations
Key Limitations: The survival benefit is modest (median 1.7 months) though HR 0.78 is clinically meaningful. Gemcitabine-based CRT is not the current preferred neoadjuvant approach (mFOLFIRINOX preferred per PRODIGE-24 data extrapolation). Less than 25% of patients received both arms as planned due to resection rate differences. Patients receiving "resectable" disease were included — benefit may concentrate in borderline resectable subgroup. Long-term OS data and subgroup analyses from the follow-up publication strengthen the results.
Clinical Context
PREOPANC is one of the first phase III trials to show OS benefit for preoperative therapy over upfront surgery in pancreatic cancer, supporting neoadjuvant approaches particularly for BRPC. Modern preoperative regimens (mFOLFIRINOX) are expected to improve on these results. Alliance A021806 (neoadjuvant vs adjuvant mFOLFIRINOX) will further define optimal sequencing.
References