SUMMARY: The American Cancer Society estimates that in 2025, about 67,440 people will be diagnosed with pancreatic cancer and 51,980 people will die of the disease. Detecting cancer at early stages can significantly increase survival rates and outcomes. Pancreatic Ductal AdenoCarcinoma (PDAC) is one of the most lethal malignancies, ranking among the leading causes of cancer-related mortality globally. A significant challenge in improving PDAC outcomes is its frequent diagnosis at an advanced stage, when therapeutic options are limited and prognosis is poor, with a 5-year survival rate of approximately 10%.
For patients with resectable or borderline-resectable Pancreatic Ductal AdenoCarcinoma (PDAC), the ideal perioperative treatment regimen remains an area of active investigation. Existing strategies vary in chemotherapy combinations, timing and duration of neoadjuvant therapy, and the use of radiation. Modified FOLFIRINOX (mFOLFIRINOX) has emerged as a standard neoadjuvant approach; however, whether more intensified or differently structured regimens can yield better outcomes is a crucial question.
The CASSANDRA trial (NCT04793932) was designed to evaluate this, comparing two chemotherapy regimens, PAXG and mFOLFIRINOX, as neoadjuvant treatment in patients with resectable or borderline-resectable PDAC.
Trial Design: A 2×2 Factorial Randomization
CASSANDRA is a multicenter, randomized, Phase 3 superiority trial enrolling 260 patients 75 years or younger with resectable/borderline resectable PDAC. Patients were stratified by site and CA19.9 level, then randomized in a 2-by-2 factorial design:
First Randomization:
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- Arm A (PAXG) N=132: Capecitabine 1250 mg/m2 PO, daily, along with Cisplatin 30 mg/m2, nab-Paclitaxel 150 mg/m2, and Gemcitabine 800 mg/m2, given biweekly.
- Arm B (mFOLFIRINOX) N=128: 5-Fluorouracil (5-FU) 2400 mg/m2, Irinotecan 150 mg/m2, Oxaliplatin 85 mg/m2, and Leucovorin 400 mg/m2 given biweekly.
Second Randomization:
After 4 months of therapy, patients without disease progression or unacceptable toxicity were re-randomized to receive 2 additional months of the same regimen either before or after surgery.
The median age was 64 yrs and both treatment groups were well balanced.
Study Endpoints
- Primary Endpoint: Event-Free Survival (EFS), defined as the absence of disease progression, recurrence, two consecutive CA19.9 increases 20% or more (separated by 4 weeks or more), unresectability, intraoperative metastasis, or death.
- Secondary Endpoints: Overall survival (OS), radiographic response, CA19.9 response, pathological response, resection rate, toxicity, and Quality of Life (QoL).
Key Findings: PAXG Demonstrates Significant EFS Benefit
- At the data cutoff of March 1, 2025, with a median follow-up of 23.9 months, PAXG significantly improved EFS compared to mFOLFIRINOX
- The 3-year EFS rate more than doubled with PAXG and was 31% compared to 13% with mFOLFIRINOX (HR=0.64; P=0.003), and the median EFS was 16 months and 10.2 months, respectively.
- The Disease Control Rate was 98% with PAXG and 91% with mFOLFIRINOX (P=0.009)
- PAXG yielded greater CA19.9 responses and pathologic downstaging compared to mFOLFIRINOX. CA19.9 reduction more than 50% was 88% versus 64% (P<0.001), resection rate was 75% versus 67% (P=0.165), and pathologic stage less than II 35% versus 23% (P=0.03), respectively.
- Notably, trends in OS also favored PAXG, though data are immature (median OS ~37 vs 26 months; HR ~0.70; P≈0.07)
The overall, toxicity profiles were similar between the two treatment groups. Patients who received PAXG did have a higher rate of grade 3-4 neutropenia, at 42% versus 29%.
Conclusion:
Neoadjuvant treatment with PAXG significantly improved EFS compared to mFOLFIRINOX in patients with resectable/borderline resectable PDAC. While PAXG shows potential as a new neoadjuvant standard, its role must be confirmed through long-term OS analysis from CASSANDRA and results from ongoing trials such as PREOPANC-3 and Alliance A021806 trials. If confirmed, neoadjuvant PAXG could become a preferred regimen for resectable or borderline-resectable PDAC, especially in patients with elevated CA19.9 or more aggressive disease phenotypes. Oncology teams should remain attentive to the evolving perioperative landscape, as long-term data and trial results continue to inform best practices.
Results of a randomized phase III trial of pre-operative chemotherapy with mFOLFIRINOX or PAXG regimen for stage I-III pancreatic ductal adenocarcinoma. Reni M, Macchini M, Orsi G, et al. J Clin Oncol 43, 2025 (suppl 17; abstr LBA4004)
