CASSANDRA supports neoadjuvant PAXG regimen for pancreatic cancer

medwireNews: Preoperative treatment with the PAXG chemotherapy regimen significantly improves the event-free survival (EFS) of patients with resectable or borderline resectable pancreatic ductal adenocarcinoma (PDAC) versus mFOLFIRINOX, show phase 3 data.

Secondary endpoints such as the disease control rate were also significantly better with PAXG (cisplatin, nab-paclitaxel, capecitabine, and gemcitabine) than with mFOLFIRINOX (modified fluorouracil, leucovorin, irinotecan, and oxaliplatin) and the safety profiles were comparable, say the researchers.

They therefore write in The Lancet that “CASSANDRA sets PAXG as a new standard regimen for preoperative treatment” for this patient population.

The trial enrolled 260 patients aged 18–75 years (median 63–65 years, 48–52% women) who had stage I–III PDAC that was considered to be resectable or borderline resectable from 17 Italian hospitals. They were randomly assigned to receive either PAXG (n=132) or mFOLFIRINOX (n=128) for 4 months, with the details of the regimens as below:

• PAXG – a total daily capecitabine dose of 1250 mg/m² given in two 625 mg/m² doses, and intravenous cisplatin 30 mg/m², nab-paclitaxel 150 mg/m², and gemcitabine 800 mg/m² given every 14 days
• mFOLFIRINOX – intravenous fluorouracil 2400 mg/m², leucovorin 400 mg/m², irinotecan 150 mg/m², and oxaliplatin 85 mg/m² given every 14 days

Participants without disease progression or limiting toxicity at 4 months were then randomly assigned to receive a further 2 months of the same chemotherapy regimen either before or after surgery.

The current report focuses on the results of the first randomization, which showed that after a median follow-up of 28.5 months, the median EFS was significantly longer in the PAXG than mFOLFIRINOX group, at 16.0 versus 10.2 months.

This translated into a hazard ratio for an event of 0.63 in favor of PAXG, where an event was defined as radiologic progression, disease recurrence, two consecutive CA19-9 increases, unresectability, intraoperative metastasis, or death.

The 1-year EFS rate in the PAXG arm was 61% compared with 45% in the mFOLFIRINOX arm, while the corresponding 3-year rates were 33% and 13%.

The investigators also found that “[t]he rates of disease control (radiological response or stable disease), CA19-9 reduction, early pathological stage, resections without nodal infiltration at pathological report, intraoperative or early postoperative metastases were significantly better in the PAXG group than in the mFOLFIRINOX group.”

Adverse events (AEs) of at least grade 3 occurred in 66% of patients treated with PAXG and 61% of those given mFOLFIRINOX. The incidence of most grade 3–4 AEs was comparable, apart from neutropenia, which was more significantly common with PAXG (43 vs 29%).

And the team points out that “in terms of all-grade toxicities, the safety profile was better in the PAXG group than in the mFOLFIRINOX group.”

Quality of life was assessed using the EORTC 30-item Quality-of-Life Questionnaireand the 26-item EORTC questionnaire for patients with PDAC. These did not reveal any significant differences between the arms at either baseline or month 4, with the exception of a trend toward a worse score in the symptoms scale for nausea and vomiting among patients who received mFOLFIRINOX.

Of note, the proportion of patients that did not complete the questionnaires due to disease progression or treatment withdrawal due to toxicity was significantly lower in the PAXG than mFOLFIRINOX group (5 vs 16%).

“Intuitively, these circumstances are probably related to a worse quality of life and the absence of data from these patients could have masked a larger difference between groups,” highlight Michele Reni (IRCCS San Raffaele Scientific Institute, Milan, Italy) and co-authors.

The authors of an accompanying commentary draw attention to certain limitations such as the fact that “the use of neoadjuvant mFOLFIRINOX in resectable PDAC has not been accepted as superior to surgery first followed by adjuvant chemotherapy,” and that “EFS has not been validated as a surrogate for overall survival in early-stage PDAC.”

Nevertheless, Grainne O’Kane (St Vincent’s UCD Cancer Centre, Dublin, Ireland) and co-commentators conclude: “The quadruplet regimen of PAXG is a new option in the neoadjuvant setting for fit patients younger than 75; however, validation of the promising EFS results with mature overall survival data is needed.”

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2025 Springer Healthcare Ltd, part of Springer Nature

Lancet 2025; doi: 10.1016/S0140-6736(25)01685-X
Lancet 2025; doi:10.1016/S0140-6736(25)01864-1