Comparing neoadjuvant regimens in resectable and borderline resectable pancreatic cancer: lessons from PREOPANC-2

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with limited long-term survival despite advances in surgical techniques and systemic therapy over the past decades (1). Even among patients initially classified as having localized disease, it is increasingly recognized as a systemic malignancy with early dissemination and high recurrence rates after surgery (1,2). This biological framework provides a compelling rationale for neoadjuvant strategies; however, their role has not been firmly established (2,3). Clinical acceptance has been greater in the borderline resectable setting, largely informed by the results of the PREOPANC-1 trial, in which the benefits of neoadjuvant therapy were driven primarily by this subgroup, whereas no comparable benefit was observed in resectable tumors (4-6).

In this context, PREOPANC-2, a multicenter, open-label, randomized phase III trial conducted in the Netherlands by the Dutch Pancreatic Cancer Group, compared two neoadjuvant strategies in patients with resectable and borderline resectable PDAC (7). Patients were randomized to receive either neoadjuvant full-dose FOLFIRINOX (oxaliplatin 85 mg/m², irinotecan 180 mg/m², leucovorin 400 mg/m², and fluorouracil 400 mg/m² bolus followed by 2,400 mg/m² continuous infusion over 46 h, every 2 weeks) followed by surgery without adjuvant therapy or neoadjuvant gemcitabine-based chemoradiotherapy (gemcitabine 1,000 mg/m² on days 1, 8, and 15 every 28 days for two cycles, with concurrent radiotherapy to a total dose of 36 Gy delivered in 15 fractions) followed by surgery and adjuvant gemcitabine.

Given its design, this trial should be interpreted strictly as a head-to-head comparison of neoadjuvant strategies rather than an assessment of neoadjuvant therapy as a treatment paradigm or treatment intensification versus treatment de-escalation (7). Neither of the evaluated regimens represents the contemporary standard of care for resectable disease (surgery upfront), and the trial did not include a control arm reflecting current management with upfront surgery followed by adjuvant chemotherapy FOLFIRINOX. In addition, approximately 65% of enrolled patients had resectable disease. Collectively, these design features limit the extent to which the results can be extrapolated to routine clinical practices.

Marked biological heterogeneity was not considered in the PREOPANC-2. The trial did not incorporate molecular features associated with patterns of disease dissemination into patient selection or stratification (8-10). Germline or somatic BRCA testing was not reported, despite the current consensus recommending testing at diagnosis and evidence that homologous recombination-deficient tumors derive greater benefit from platinum-based chemotherapy (11). Upfront transcriptomic profiling is technically feasible and clinically informative yet was not integrated into this trial (9,12). Disease progression was not categorized as locoregional or systemic failure, precluding the assessment of whether biologically distinct patterns of progression might differentially benefit from specific neoadjuvant approaches.

PREOPANC-2 did not demonstrate a survival advantage for either neoadjuvant strategy. On an intention-to-treat basis, the study failed to meet its primary endpoint, with no statistically significant difference in median overall survival between the treatment arms (21.9 months with FOLFIRINOX vs. 21.3 months with chemoradiotherapy; hazard ratio, 0.88; 95% confidence interval: 0.69–1.13; P=0.32). The secondary endpoints, including progression-free survival, overall resection rate, R0 resection rate, and pathological response, were comparable between the groups. Although a higher proportion of ypN0 resections were observed in the chemoradiotherapy arm, this apparent pathological advantage failed to translate into a survival benefit. Subgroup analyses revealed no significant interactions based on resectability status, with no overall survival advantage observed in either arm (7). The lack of survival estimates stratified by resectability status and surgical completion limits meaningful inter-trial comparisons with modern adjuvant studies (13).

These neutral survival results were mirrored by the absence of meaningful differences in the operative outcomes. Resection rates, margin-negative resections, postoperative morbidity, and mortality were comparable, indicating that both neoadjuvant strategies are surgically feasible when performed in experienced centers (7). Disease progression during neoadjuvant therapy remains a critical concern, with 18% of patients in the FOLFIRINOX arm and 20% in the chemoradiotherapy arm unable to undergo resection due to progression, highlighting the inherent risk of preoperative treatment in a biologically aggressive malignancy (7,14).

Treatment-related toxicity was substantial, with higher rates of dose reduction and treatment discontinuation observed in the FOLFIRINOX arm. Despite this, the proportions of patients experiencing at least one adverse event or grade 3 or higher serious adverse event were similar between the treatment groups, and the overall dropout rates did not differ meaningfully between the arms (7). It is unclear whether a modified FOLFIRINOX regimen, which is more commonly used in contemporary practice and is associated with improved tolerability, would have resulted in different adherence patterns or outcomes (15,16).

The role of radiotherapy in neoadjuvant strategies for localized PDAC remains unclear. In PREOPANC-2, radiotherapy was exclusively included in the comparator arm, complicating the attribution of any observed effects to radiotherapy itself. Substantial heterogeneity across studies in radiation dose, fractionation, target volumes, and sequencing with systemic therapy has limited a coherent assessment of their contributions. This uncertainty is reinforced by the absence of any demonstrated overall survival benefit and by the Alliance A021501 trial, in which the addition of radiotherapy to systemic therapy was associated with inferior survival (17-19).

In summary, PREOPANC-2 adds to the heterogeneous body of evidence evaluating neoadjuvant therapy for PDAC (Table 1). Studies frequently combine resectable, borderline resectable, and locally advanced disease and mix chemotherapy with chemoradiotherapy, pooling gemcitabine-based and multi-agent regimens, limiting interpretability (5,20). By directly comparing two neoadjuvant strategies, the trial reinforces that empirical modification or substitution of chemotherapy regimens alone is unlikely to meaningfully alter outcomes in patients with localized PDAC. This conclusion aligns with other negative perioperative trials, including NORPACT-1 and NEONAX, in which alternative neoadjuvant chemotherapy strategies failed to improve survival (13,21). Likewise, the SWOG S1505 trial demonstrated that both FOLFIRINOX and gemcitabine-nab-paclitaxel yielded insufficient efficacy to justify continued evaluation in unselected populations (16).

Attention is now shifting toward strategies that directly reflect the biological diversity of PDAC. Emerging genomic and transcriptomic approaches, designed to capture distinct tumor phenotypes through broader molecular coverage, are becoming increasingly accessible. Recent studies incorporating GATA6-based stratification in the neoadjuvant setting provide an early illustration of how biology-driven selection may translate into more meaningful therapeutic benefits, as recently shown in the pilot NeoPancONE study (22). Within this context, this trial represents an important reference point, reinforcing the need for biologically informed trial designs. Technologies such as circulating tumor DNA could also inform diseases with better or worse prognosis, helping selection of more suitable upfront treatment strategies for patients with localized pancreatic cancer (22-24). Finally, more intensive chemotherapy combinations like PAXG evaluated at the CASSANDRA trial or new molecules as KRAS inhibitors can also soon change paradigms (25,26).

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Pancreatic Cancer. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://apc.amegroups.com/article/view/10.21037/apc-26-0006/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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References

1. Usón PL Junior, França MS, Rodrigues HV, et al. Higher overall survival in metastatic pancreatic cancer: the impact of where and how treatment is delivered. Einstein (Sao Paulo) 2015;13:347-51. [Crossref] [PubMed]
2. Stoop TF, Javed AA, Oba A, et al. Pancreatic cancer. Lancet 2025;405:1182-202. [Crossref] [PubMed]
3. Khorana AA, McKernin SE, Berlin J, et al. Potentially Curable Pancreatic Adenocarcinoma: ASCO Clinical Practice Guideline Update. J Clin Oncol 2019;37:2082-8. [Crossref] [PubMed]
4. Tempero MA, Malafa MP, Al-Hawary M, et al. Pancreatic Adenocarcinoma, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2021;19:439-57. [Crossref] [PubMed]
5. Versteijne E, Suker M, Groothuis K, et al. Preoperative Chemoradiotherapy Versus Immediate Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Results of the Dutch Randomized Phase III PREOPANC Trial. J Clin Oncol 2020;38:1763-73. [Crossref] [PubMed]
6. Versteijne E, van Dam JL, Suker M, et al. Neoadjuvant Chemoradiotherapy Versus Upfront Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Long-Term Results of the Dutch Randomized PREOPANC Trial. J Clin Oncol 2022;40:1220-30. [Crossref] [PubMed]
7. Janssen QP, van Dam JL, van Bekkum ML, et al. 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 2025;26:1346-56. [Crossref] [PubMed]
8. Iacobuzio-Donahue CA, Fu B, Yachida S, et al. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol 2009;27:1806-13. [Crossref] [PubMed]
9. Knox JJ, Jang GH, Grant RC, et al. Whole genome and transcriptome profiling in advanced pancreatic cancer patients on the COMPASS trial. Nat Commun 2025;16:5919. [Crossref] [PubMed]
10. Dekker EN, Janssen QP, van Dam JL, et al. Blood Sample Collection in Randomized Controlled Trials for Biomarker Discovery and Validation: Experience of the PREOPANC-2 Trial. Ann Surg Oncol 2025;32:5092-101. [Crossref] [PubMed]
11. O'Reilly EM, Lee JW, Zalupski M, et al. Randomized, Multicenter, Phase II Trial of Gemcitabine and Cisplatin With or Without Veliparib in Patients With Pancreas Adenocarcinoma and a Germline BRCA/PALB2 Mutation. J Clin Oncol 2020;38:1378-88. [Crossref] [PubMed]
12. Knox JJ, O'Kane G, King D, et al. PASS-01: Randomized Phase II Trial of Modified FOLFIRINOX Versus Gemcitabine/Nab-Paclitaxel and Molecular Correlatives for Previously Untreated Metastatic Pancreatic Cancer. J Clin Oncol 2025;43:3355-68. [Crossref] [PubMed]
13. Labori KJ, Bratlie SO, Andersson B, et al. Neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer (NORPACT-1): a multicentre, randomised, phase 2 trial. Lancet Gastroenterol Hepatol 2024;9:205-17. [Crossref] [PubMed]
14. Uson PLS Junior, Carvalho L, Fernandes MLC, et al. Neoadjuvant chemotherapy or upfront surgery in localized pancreatic cancer: a contemporary analysis. Sci Rep 2022;12:13592. [Crossref] [PubMed]
15. Conroy T, Hammel P, Hebbar M, et al. FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer. N Engl J Med 2018;379:2395-406. [Crossref] [PubMed]
16. Sohal DPS, Duong M, Ahmad SA, et al. Efficacy of Perioperative Chemotherapy for Resectable Pancreatic Adenocarcinoma: A Phase 2 Randomized Clinical Trial. JAMA Oncol 2021;7:421-7. [Crossref] [PubMed]
17. Stoop TF, Theijse RT, Seelen LWF, et al. Preoperative chemotherapy, radiotherapy and surgical decision-making in patients with borderline resectable and locally advanced pancreatic cancer. Nat Rev Gastroenterol Hepatol 2024;21:101-24. [Crossref] [PubMed]
18. Biankin AV, Waddell N, Kassahn KS, et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 2012;491:399-405. [Crossref] [PubMed]
19. Katz MHG, Shi Q, Meyers J, et al. Efficacy of Preoperative mFOLFIRINOX vs mFOLFIRINOX Plus Hypofractionated Radiotherapy for Borderline Resectable Adenocarcinoma of the Pancreas: The A021501 Phase 2 Randomized Clinical Trial. JAMA Oncol 2022;8:1263-70. [Crossref] [PubMed]
20. Cloyd JM, Heh V, Pawlik TM, et al. Neoadjuvant Therapy for Resectable and Borderline Resectable Pancreatic Cancer: A Meta-Analysis of Randomized Controlled Trials. J Clin Med 2020;9:1129. [Crossref] [PubMed]
21. Seufferlein T, Uhl W, Kornmann M, et al. Perioperative or only adjuvant gemcitabine plus nab-paclitaxel for resectable pancreatic cancer (NEONAX)—a randomized phase II trial of the AIO pancreatic cancer group. Ann Oncol 2023;34:91-100. [Crossref] [PubMed]
22. Tie J, Wang Y, Tomasetti C, et al. Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer. Sci Transl Med 2016;8:346ra92. [Crossref] [PubMed]
23. Groot VP, Mosier S, Javed AA, et al. Circulating Tumor DNA as a Clinical Test in Resected Pancreatic Cancer. Clin Cancer Res 2019;25:4973-84. [Crossref] [PubMed]
24. Botrus G, Uson PLS Junior, Raman P, et al. Circulating Cell-Free Tumor DNA in Advanced Pancreatic Adenocarcinoma Identifies Patients With Worse Overall Survival. Front Oncol 2021;11:794009. [Crossref] [PubMed]
25. Garrido-Laguna I, Wolpin BM, Park W, et al. Safety, efficacy, and on-treatment circulating tumor DNA (ctDNA) changes from a phase 1 study of RMC-6236, a RAS(ON) multi-selective, tri-complex inhibitor, in patients with RAS mutant pancreatic ductal adenocarcinoma (PDAC). J Clin Oncol 2025;43:722.
26. Reni M, Macchini M, Orsi G, et al. Preoperative mFOLFIRINOX versus PAXG for stage I-III resectable and borderline resectable pancreatic ductal adenocarcinoma (PACT-21 CASSANDRA): results of the first randomisation analysis of a randomised, open-label, 2 × 2 factorial phase 3 trial. Lancet 2026;406:2945-56. [Crossref] [PubMed]