Clinical trialPhase 3Pancreatic cancer

Neoadjuvant FOLFIRINOX versus neoadjuvant gemcitabine-based chemoradiotherapy in resectable and borderline resectable pancreatic cancer (PREOPANC-2): a multicentre, open-label, phase 3 randomised trial

Lancet Oncol · 2025375 patients randomised (188 FOLFIRINOX, 187 chemoradiotherapy); 369 patients in the modified intention-to-treat population

Janssen QP, van Dam JL, van Bekkum ML, et al. Lancet Oncol. 2025. 26:1346-1356

Study type: Clinical trial
Study name: PREOPANC-2
Phase: Phase 3
Design: Open-label, nationwide, investigator-initiated randomised trial at 19 centres in the Netherlands (Dutch Pancreatic Cancer Group); 1:1 randomisation by minimisation, stratified by resectability status and centre; EudraCT: 2017-002036-17
Sample size: 375 patients randomised (188 FOLFIRINOX, 187 chemoradiotherapy); 369 patients in the modified intention-to-treat population
Source: Lancet Oncol · 2025

In plain words

In pancreatic cancer that can be removed by surgery, or is borderline for surgery, many doctors give treatment before the operation to improve the chance that surgery succeeds and the disease is controlled. The PREOPANC-2 study in the Netherlands compared two approaches: strong three-drug FOLFIRINOX chemotherapy before surgery, or gemcitabine with a short course of radiotherapy before surgery followed by gemcitabine after surgery. Survival was almost the same in both groups (about 22 months on average), and serious side effects were seen in both groups; severe diarrhoea was much more common with FOLFIRINOX. The conclusion is that both approaches are acceptable options, and your doctor will choose one based on your situation.

Key results

21.9 months vs 21.3 months

Median overall survival

FFX vs CRT; HR 0.88 (95% CI 0.69-1.13); p=0.32; median follow-up 42.3 months

67% vs 60%

Grade 3 or higher adverse events

117 vs 106 patients; p=0.20

49% vs 43%

Serious adverse events

85 vs 75 patients; p=0.26

23% vs 1%

Grade 3–4 diarrhoea

41 of 175 vs 2 of 176

2 patients (1%) vs 1 patient (1%)

Treatment-related death

FFX: multi-organ failure, intestinal mucositis; CRT: upper GI haemorrhage

Drugs in this study:Fluorouracil (5-FU)Gemcitabine (Gemzar)Irinotecan (Camptosar)Oxaliplatin (Eloxatin)

Dose and schedule cards

Neoadjuvant FOLFIRINOX (PREOPANC-2)

Resectable or borderline resectable pancreatic cancer; WHO performance status 0–1Cycle length: Every 14 daysOn the page “Pancreatic cancer” · Adjuvant (postoperative) and neoadjuvant (preoperative) therapy

Resectable or borderline resectable pancreatic cancer; WHO performance status 0–1

Drug	Dose	Route	Schedule
Oxaliplatin	85 mg/m²	IV over 2 hours	Day 1
Irinotecan	180 mg/m²	IV over 90 minutes	Day 1
Leucovorin	400 mg/m²	IV over 2 hours	Day 1
Fluorouracil (bolus)	400 mg/m²	IV bolus	Day 1
Fluorouracil (infusion)	2400 mg/m²	IV, 46-hour continuous infusion	Starting Day 1

Cycle length: Every 14 days
Duration: 8 cycles, then surgery; no adjuvant therapy after surgery

Doses and schedule from PREOPANC-2; infusion durations per the FDA labels. In resectable disease without high-risk features, the benefit of neoadjuvant therapy has not been established.

On the page “Pancreatic cancer” · Adjuvant (postoperative) and neoadjuvant (preoperative) therapy

Neoadjuvant gemcitabine-based chemoradiotherapy (PREOPANC)

Resectable or borderline resectable pancreatic cancerCycle length: Every 28 daysOn the page “Pancreatic cancer” · Adjuvant (postoperative) and neoadjuvant (preoperative) therapy

Resectable or borderline resectable pancreatic cancer

Drug	Dose	Route	Schedule
Preoperative: 3 cycles of 28 days
Gemcitabine	1000 mg/m²	IV	Cycles 1 and 3: Days 1 and 8; Cycle 2: Days 1, 8 and 15
Hypofractionated radiotherapy	36 Gy in 15 fractions	External beam	During cycle 2 only
Postoperative: 4 cycles
Adjuvant gemcitabine		IV

Cycle length: Every 28 days
Duration: 3 cycles before surgery, surgery, then 4 cycles of adjuvant gemcitabine

Doses and schedule from PREOPANC-2 (chemoradiotherapy arm); survival evidence compared with upfront surgery: PREOPANC.

On the page “Pancreatic cancer” · Adjuvant (postoperative) and neoadjuvant (preoperative) therapy

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Preoperative FOLFIRINOX (FFX group)

Every 14 days, 8 cycles: oxaliplatin 85 mg/m² IV, irinotecan 180 mg/m² IV, leucovorin 400 mg/m² IV, then fluorouracil (5-FU) 400 mg/m² IV bolus followed by 2400 mg/m² continuous IV infusion over 46 hours; then surgery, with no adjuvant therapy after surgery.

2Preoperative gemcitabine-based chemoradiotherapy (CRT group)

Three preoperative cycles of gemcitabine (1000 mg/m² IV on days 1, 8 and 15 of each 28-day cycle, and only on days 1 and 8 in the first and third cycles) with hypofractionated radiotherapy (36 Gy in 15 fractions) during the second cycle only; then surgery and four cycles of adjuvant gemcitabine after surgery.

Source of the regimen details: Abstract of the paper

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients aged 18 or older with resectable or borderline resectable pancreatic ductal adenocarcinoma (PDAC) and WHO performance status 0 or 1. Enrolment from 5 June 2018 to 28 January 2021; 208 (56%) men and 161 (44%) women.

Endpoints

Primary outcome: overall survival in the modified intention-to-treat population (after excluding ineligible patients). Adverse events were also reported.

Safety and side effects

Most common grade 3–4 adverse events: neutropenia (43 of 175 [25%] in the FFX group versus 38 of 176 [22%] in the CRT group), diarrhoea (41 [23%] versus 2 [1%]) and leucopenia (14 [8%] versus 26 [15%]). Serious adverse events occurred in 85 patients (49%) in the FFX group and 75 patients (43%) in the CRT group (p=0.26), and grade 3 or higher adverse events in 117 (67%) versus 106 (60%) patients (p=0.20). Treatment-related deaths: 2 patients (1%) in the FFX group (multi-organ failure and intestinal mucositis) and 1 patient (1%) in the CRT group (upper gastrointestinal haemorrhage).

Clinical significance and place in guidelines

PREOPANC-2 showed that preoperative FOLFIRINOX (without adjuvant therapy) does not improve overall survival in resectable and borderline resectable PDAC compared with preoperative gemcitabine-based chemoradiotherapy followed by adjuvant gemcitabine. The authors concluded that both preoperative regimens can be considered in these patients. Together with NORPACT-1 (which showed no benefit of preoperative FOLFIRINOX over upfront surgery in resectable tumours), this study adds to the debate about the best preoperative strategy in resectable pancreatic cancer.

Limitations

Open-label trial; resectable and borderline resectable patients were analysed together. The two arms differed in several components at once (type of chemotherapy, radiotherapy, and presence or absence of adjuvant therapy), so the contribution of each component cannot be assessed separately. All centres were in one country (the Netherlands). The abstract reports only the primary outcome and safety; resection rates and secondary outcomes are not given.

Original article (DOI)PubMed

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.