Integrating surgery into multimodal treatment for locally advanced pancreatic cancer: beyond the boundaries of systemic therapy

We read with great interest the recently published results of the PRODIGE 29-UCGI 26 (NEOPAN) trial, a phase III study comparing modified folinic acid, fluorouracil, irinotecan, oxaliplatin (mFOLFIRINOX) with gemcitabine in patients with locally advanced pancreatic cancer (LAPC) (1). While mFOLFIRINOX significantly improved progression-free survival, the reported median overall survival was comparable between the two treatment arms (15.7 vs. 15.4 months), underscoring the limited impact of systemic therapy alone in this setting.

Notably, only a small proportion of patients in the NEOPAN trial underwent surgical resection—9 out of 171 patients (four in the gemcitabine group and five in the mFOLFIRINOX group). This finding reflects the ongoing difficulty in converting LAPC into a resectable state, even with intensified chemotherapy. A median overall survival of approximately 15 months, although somewhat improved over the 11 months typically observed in metastatic disease and fit patients (2), remains modest in the context of potentially curative treatment.

The CONKO-007 and NEOLAP trials reported resection rates of 23% and 40%, respectively, in this setting, and single-center studies have shown that neoadjuvant treatment with mFOLFIRINOX can result in secondary resectability in up to 60% of LAPC patients, highlighting the potential of aggressive systemic therapy to enable surgery in selected cases (3-5).

One of the main surgical challenges in LAPC is performing vascular resections and reconstructions, particularly of the superior mesenteric artery and hepatic artery. Given the technical complexity of vascular resections—ranging from venous interposition grafts to complex arterial reconstructions and the management of intraoperative complications—extensive expertise in vascular surgery is essential. Surgeons performing these procedures must possess advanced skills across the spectrum of vascular techniques to ensure safe and effective restoration of vascular continuity and to maximize oncologic outcomes.

Venous resections have been considered safe and not inferior to standard pancreatic resections for more than a decade, with comparable perioperative outcomes and long-term survival in appropriately selected patients. Arterial resections, when performed in high-volume centers with appropriate expertise, have been shown to be safe and feasible in selected patients with locally advanced pancreatic cancer (5,6). When compared to palliative treatments, arterial resections, performed as part of a curative-intent strategy, are associated with a clear survival benefit (7). In specialized centers, vascular, particularly arterial resections even with complex visceral artery debranching and extended multivisceral procedures are increasingly considered standard components of multimodal treatment strategies for LAPC in appropriately selected patients (8,9).

Recent advances in precision oncology have underscored the growing importance of tumor biology in guiding treatment decisions for LAPC. Beyond anatomical resectability, biomarkers such as carbohydrate antigen 19.9 (CA19.9) levels have been shown to correlate with tumor burden and prognosis, potentially aiding in the selection of patients most likely to benefit from multimodal treatment strategies (10,11).

Furthermore, emerging technologies such as genomic and transcriptomic profiling provide deeper insights into tumor behavior, therapeutic vulnerabilities, and resistance mechanisms. Liquid biopsy techniques, including circulating tumor DNA (ctDNA) and circulating tumor cells, offer minimally invasive methods for monitoring disease dynamics and detecting actionable mutations (12,13). These approaches enable the identification of biologically distinct subgroups who may respond more favorably to specific systemic therapies or targeted agents. Incorporating such biological and molecular data into patient selection frameworks represents a shift toward more individualized, evidence-based decision-making in the management of LAPC.

These observations also underscore the urgent need to incorporate surgical strategies into multimodal treatment concepts whenever feasible, with the aim of achieving meaningful improvements in long-term survival. A more refined understanding of the criteria for surgical candidacy in LAPC is essential to guide individualized treatment planning.

Acknowledgments

None.

Footnote

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Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-342/coif). The authors have no conflicts of interest to declare.

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References

1. Ducreux M, Desgrippes R, Rinaldi Y, et al. PRODIGE 29-UCGI 26 (NEOPAN): A Phase III Randomized Trial Comparing Chemotherapy With FOLFIRINOX or Gemcitabine in Locally Advanced Pancreatic Carcinoma. J Clin Oncol 2025;43:2255-64. [Crossref] [PubMed]
2. Nichetti F, Rota S, Ambrosini P, et al. NALIRIFOX, FOLFIRINOX, and Gemcitabine With Nab-Paclitaxel as First-Line Chemotherapy for Metastatic Pancreatic Cancer: A Systematic Review and Meta-Analysis. JAMA Netw Open 2024;7:e2350756. [Crossref] [PubMed]
3. Hackert T, Sachsenmaier M, Hinz U, et al. Locally Advanced Pancreatic Cancer: Neoadjuvant Therapy With Folfirinox Results in Resectability in 60% of the Patients. Ann Surg 2016;264:457-63. [Crossref] [PubMed]
4. Kunzmann V, Siveke JT, Algül H, et al. Nab-paclitaxel plus gemcitabine versus nab-paclitaxel plus gemcitabine followed by FOLFIRINOX induction chemotherapy in locally advanced pancreatic cancer (NEOLAP-AIO-PAK-0113): a multicentre, randomised, phase 2 trial. Lancet Gastroenterol Hepatol 2021;6:128-38. [Crossref] [PubMed]
5. Fietkau R, Ghadimi M, Grützmann R, et al. Randomized phase III trial of induction chemotherapy followed by chemoradiotherapy or chemotherapy alone for nonresectable locally advanced pancreatic cancer: First results of the CONKO-007 trial. J Clin Oncol 2022;40:4008.
6. Loos M, Kester T, Klaiber U, et al. Arterial Resection in Pancreatic Cancer Surgery: Effective After a Learning Curve. Ann Surg 2022;275:759-68. [Crossref] [PubMed]
7. Del Chiaro M, Rangelova E, Halimi A, et al. Pancreatectomy with arterial resection is superior to palliation in patients with borderline resectable or locally advanced pancreatic cancer. HPB (Oxford) 2019;21:219-25. [Crossref] [PubMed]
8. Rebelo A, Büdeyri I, Heckler M, et al. Systematic review and meta-analysis of contemporary pancreas surgery with arterial resection. Langenbecks Arch Surg 2020;405:903-19. [Crossref] [PubMed]
9. Ronellenfitsch U, Michalski CW, Michl P, et al. Pre-operative/Neoadjuvant Therapy and Vascular Debranching Followed by Resection for Locally Advanced Pancreatic Cancer (PREVADER): Clinical Feasibility Trial. Front Med (Lausanne) 2021;8:588375. [Crossref] [PubMed]
10. van Veldhuisen E, Vogel JA, Klompmaker S, et al. Added value of CA19-9 response in predicting resectability of locally advanced pancreatic cancer following induction chemotherapy. HPB (Oxford) 2018;20:605-11. [Crossref] [PubMed]
11. Strobel O, Berens V, Hinz U, et al. Resection after neoadjuvant therapy for locally advanced, "unresectable" pancreatic cancer. Surgery 2012;152:S33-42. [Crossref] [PubMed]
12. Riva F, Dronov OI, Khomenko DI, et al. Clinical applications of circulating tumor DNA and circulating tumor cells in pancreatic cancer. Mol Oncol 2016;10:481-93. [Crossref] [PubMed]
13. Habib JR, Yin L, Yu J. Pancreatic ductaladenocarcinoma: the role of circulating tumor DNA. J Pancreatol 2019;2:72-5.