# Chemotherapy before surgery for every resectable pancreatic cancer, settled by the two perioperative trials rather than assumed

Source: https://onco.cc/ideas/idea-pdac-neoadjuvant-chemotherapy-for-all-resectable-disease/  
OnCo record `idea-pdac-neoadjuvant-chemotherapy-for-all-resectable-disease` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Giving chemotherapy before the operation is standard when the tumour is borderline operable, but for tumours that can be removed straight away two trials have failed to show it beats operating first. Two more, one Dutch and one American, are directly comparing chemotherapy before and after surgery with chemotherapy after alone; the proposal is to wait for them and to pool them.

## Summary

PREOPANC (2020) missed its primary endpoint (16.0 versus 14.3 months) but raised R0 resection from 40 to 71 percent and showed a five-year benefit in 2022; ESPAC-5 and Alliance A021501 supported neoadjuvant treatment for borderline resectable disease. For resectable disease, NORPACT-1 (2024) did not favour neoadjuvant FOLFIRINOX over upfront surgery and PREOPANC-2 (2025, 375 patients) found neoadjuvant FOLFIRINOX no better than gemcitabine chemoradiotherapy (21.9 versus 21.3 months), with neither trial using the current adjuvant standard of six months of modified FOLFIRINOX as comparator. The argument for neoadjuvant treatment for all is that a third of patients never receive adjuvant chemotherapy after a Whipple operation and that early systemic treatment tests biology before a major operation; the argument against is that FOLFIRINOX before surgery delays or prevents the operation in patients who progress and that PRODIGE 24 already delivers a median of 53.5 months in those who get it. PREOPANC-3 (378 estimated, primary completion January 2027) and Alliance A021806 (358, December 2028) compare perioperative with adjuvant modified FOLFIRINOX and are the trials that can settle it; a pre-planned pooled analysis, with resection rate, R0 rate and receipt of all planned chemotherapy as secondary endpoints, would give the answer more power than either alone.

## Fields

- Kind: Idea
- Last checked: 2026-09-24
- Tags: pancreatic-evidence
- Hypothesis: Perioperative modified FOLFIRINOX improves overall survival over adjuvant modified FOLFIRINOX in resectable pancreatic cancer by a hazard ratio of 0.75 or better, and the benefit is carried by patients who would otherwise not have completed adjuvant treatment.
- Rationale: The comparator problem in NORPACT-1 and PREOPANC-2 is fixed in the two running trials; individual patient pooling across 736 patients gives power for the subgroup (borderline versus clearly resectable, CA 19-9 high versus low) that decides practice.
- Proposed test: PREOPANC-3 and Alliance A021806 readouts (2027 to 2029) with a pre-registered pooled individual patient analysis; secondary endpoints resection rate, R0 rate, proportion receiving all planned chemotherapy, quality of life.
- Maturity: being-tested-at-scale
- Actor: research

## Sources

- ClinicalTrials.gov NCT04927780: https://clinicaltrials.gov/study/NCT04927780
- ClinicalTrials.gov NCT04340141: https://clinicaltrials.gov/study/NCT04340141
- PREOPANC-2 (Lancet Oncol 2025): https://europepmc.org/article/MED/40945523

## Connected records

- ideas: [RAS(ON) inhibitors to convert unresectable pancreatic cancer to resectable](https://onco.cc/ideas/idea-ras-inhibitor-neoadjuvant-pdac/)
- roadmaps: [Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question](https://onco.cc/roadmaps/pancreatic-roadmap/), [Surgery roadmap: radical operations → less surgery → no surgery when a drug has done the work](https://onco.cc/roadmaps/surgery-roadmap/)
- cancers: [Borderline resectable pancreatic ductal adenocarcinoma](https://onco.cc/cancers/borderline-resectable-pdac/), [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/), [Resectable pancreatic ductal adenocarcinoma](https://onco.cc/cancers/resectable-pdac/)
- technologies: [Cytotoxic chemotherapy](https://onco.cc/technologies/cytotoxic-chemotherapy/)
- drugs: [FOLFIRINOX / mFOLFIRINOX](https://onco.cc/drugs/folfirinox/)
- terms: [Neoadjuvant / adjuvant / perioperative](https://onco.cc/terms/neoadjuvant-adjuvant/), [Resectable, borderline resectable and unresectable](https://onco.cc/terms/resectability/), [Resection margins (R0 / R1 / R2)](https://onco.cc/terms/resection-margins/), [Total neoadjuvant therapy (TNT, rectal cancer)](https://onco.cc/terms/total-neoadjuvant-therapy/)
- trials: [ESPAC-5](https://onco.cc/trials/espac-5/), [PREOPANC-1](https://onco.cc/trials/preopanc/), [PRODIGE 24 / CCTG PA6](https://onco.cc/trials/prodige-24/)
- bottlenecks: [Surgery and radiotherapy cure most, get least](https://onco.cc/bottlenecks/b-surgery-radiation-innovation/), [Trial design, endpoints and cost](https://onco.cc/bottlenecks/b-trial-design/)
- key papers: [Alliance A021501: preoperative modified FOLFIRINOX with or without hypofractionated radiotherapy for borderline resectable pancreatic cancer](https://onco.cc/key-papers/paper-alliance-a021501-mfolfirinox-radiotherapy-borderline-resectable-jama-oncol-2022/), [Five-Year Outcomes of FOLFIRINOX vs Gemcitabine as Adjuvant Therapy for Pancreatic Cancer: A Randomized Clinical Trial](https://onco.cc/key-papers/paper-prodige-24-five-year-outcomes-jama-oncol-2022/), [Neoadjuvant FOLFIRINOX versus neoadjuvant gemcitabine-based chemoradiotherapy in resectable and borderline resectable pancreatic cancer (PREOPANC-2): a multicentre, open-label, phase 3 randomised trial](https://onco.cc/key-papers/paper-preopanc-2-neoadjuvant-folfirinox-vs-chemoradiotherapy-lancet-oncol-2025/), [NORPACT-1: neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer](https://onco.cc/key-papers/paper-norpact-1-neoadjuvant-folfirinox-labori-lancet-gastroenterol-hepatol-2024/), [Preoperative Chemoradiotherapy Versus Immediate Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Results of the Dutch Randomized Phase III PREOPANC Trial](https://onco.cc/key-papers/paper-preopanc-preoperative-chemoradiotherapy-jco-2020/)

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