Short-term versus long-course neoadjuvant chemotherapy for resectable and borderline resectable pancreatic ductal adenocarcinoma (PACT-21 CASSANDRA): results from the second randomisation analysis of a randomised, open-label, 2 × 2 factorial phase 3 trial

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• Picked for Pediatric Surgery (top studies of the week, 20 September 2026): Ranked by evidence level and journal quartile
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• Picked for Bariatric and Metabolic Surgery (top studies of the week, 20 September 2026): Neoadjuvant chemo for pancreatic cancer, not bariatric surgery
• Picked for Surgery (top studies of the week, 20 September 2026): Second randomisation of neoadjuvant chemo duration in pancreatic cancer
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Abstract

BACKGROUND: The first randomisation results from the PACT-21/CASSANDRA trial demonstrated that cisplatin, nab-paclitaxel, capecitabine, and gemcitabine (PAXG) is a standard neoadjuvant treatment option for resectable/borderline resectable (R/BR) pancreatic adenocarcinoma (PDAC). Here, we report the results of the second randomisation comparing long versus short pre-operative chemotherapy. METHODS: PACT-21/CASSANDRA was a 2 × 2 factorial phase 3 trial involving 17 academic hospitals across 10 regions in Italy. Eligible patients were aged 18-75 years with pathologically confirmed R/BR PDAC and were first randomly assigned to either PAXG or fluorouracil, leucovorin, irinotecan, oxaliplatin (mFOLFIRINOX). Patients without progression or limiting toxicity after 4 months were randomised to receive 2 further months of the same chemotherapy either before (long) or after (short) surgery. The trial was designed under a two-sided superiority hypothesis (H0: HR long versus short = 1.0; H1: HR ≠ 1.0). Randomisation lists were stratified according to previous chemotherapy. The primary endpoint was event-free survival (EFS) in the intention-to-treat (ITT) population. Secondary endpoints were radiological, CA19.9 and complete pathological response, R0 and N0 resections, chemotherapy dose-density, and overall survival (OS). Analyses were performed using SAS version 9.4. This trial is registered with ClinicalTrials.gov (NCT04793932) and EudraCT (2020-003080-26 and 2024-519031-42-00). FINDINGS: Between Feb 23, 2021, and Sept 03, 2024, 86 patients were assigned to long and 79 to short preoperative chemotherapy. No difference in EFS was observed between the two groups in the intention-to-treat population (unadjusted HR 0.98; 95% CI; 0.68-1.41; P = 0.90). CA19-9 response (58 [97%] of 60 versus 41 [84%] of 49 patients; P = 0.02), pathological complete response (4 [5%] of 86 versus 0 of 79 patients; P = 0.05), N0 resection rate (39 [45%] of 86 versus 21 [27%] of 79 patients; P = 0.01), and chemotherapy dose-density were improved by longer chemotherapy. OS data are not yet mature. INTERPRETATION: Long and short preoperative chemotherapy obtains similar EFS in R/BR PDAC. Future research should focus on more effective treatment regimens and explore the optimal post-operative therapy. FUNDING: MyEverest and Codice Viola (patients' associations).

Abstract as published, via PubMed.