Neoadjuvant Treatment vs Upfront Surgery for Left-Sided Pancreatic Cancer

This is a multicenter, open-label, randomized phase III trial evaluating whether neoadjuvant chemotherapy improves overall survival in patients with resectable left-sided (body/tail) pancreatic cancer compared to the current standard of upfront surgery followed by adjuvant chemotherapy. Eligible patients have histologically confirmed pancreatic adenocarcinoma located in the body or tail of the pancreas, ECOG/WHO performance status 0-2, and radiologically resectable disease according to NCCN criteria. Patients are randomized 1:1 to receive either: 1. neoadjuvant chemotherapy, followed by surgery and adjuvant therapy, or 2. upfront surgery followed by adjuvant chemotherapy. Randomization uses a minimization method with stratification by performance status, CA19-9 level, treatment center, and chemotherapy regimen. Surgery is scheduled within 4-6 weeks of randomization (control arm) or after the last neoadjuvant cycle (intervention arm). Left pancreatectomy (open or minimally invasive) with standard lymphadenectomy and splenectomy is performed with complications reported using Dindo/Clavien classification and ISGPS criteria. Radical antegrade posterior pancreatosplenectomy may be performed when needed to ensure clear margins. Tumor response to neoadjuvant therapy will be evaluated by standardized histopathological grading. Patients are followed with laboratory tests and CT imaging at the completion of adjuvant therapy and every six months thereafter until disease recurrence or up to five years after surgery. Quality of life is assessed at baseline, pre-surgery (in the neoadjuvant arm), 4 weeks post-op, and during follow-up using the EORTC QLQ-C30 and PAN26 instruments. Patients are followed for recurrence and survival every 6 months for up to 5 years. Safety is monitored per CTCAE v5.0, with SAEs and SUSARs reported per regulatory guidelines. An independent DSMB will review safety data. Blood and tumor samples will be stored for future translational research. The primary endpoint is overall survival. A total of 381 patients will be enrolled over 36 months. The trial is powered to detect a hazard ratio of 0.70 with 80% power and a 5% significance level, requiring 247 events (deaths). Analysis will follow the intention-to-treat principle using Kaplan-Meier, log-rank test, and Cox regression. Pre-specified subgroup analyses will assess factors such as age, performance status, CA19-9, and tumor characteristics.