The evolving neoadjuvant landscape in pancreatic cancer: biology often overrides anatomy in achieving margin-negative resection

The neoadjuvant treatment paradigm in localized pancreatic ductal adenocarcinoma (PDAC) has steadily gained traction over the past decade (1,2). This shift is driven by recognition of PDAC’s propensity for early subclinical metastasis, the need to ensure delivery of systemic therapy, improved surgical selection, and the theoretical benefits of reducing nodal burden and R1 resection rates (3). Accordingly, the National Comprehensive Cancer Network (NCCN) now acknowledges neoadjuvant chemotherapy as a reasonable option even for anatomically resectable PDAC (R-PDAC), reflecting an understanding that biology trumps anatomy (4). Nevertheless, many centers continue to favor upfront surgery for resectable disease, citing concerns about progression during systemic treatment, delays to surgery, and the scarcity of definitive randomized data (5). In contrast, the role of neoadjuvant therapy in borderline resectable PDAC (BR-PDAC) is far less debated: anatomical constraints and risk of margin positivity, and likelihood of microscopic dissemination make preoperative therapy the prevailing standard. Within this evolving landscape, the study by Cohen and colleagues offers timely insights into the feasibility and limitations of perioperative chemotherapy and radiotherapy across both resectability categories (6).

Published in The Oncologist, Cohen et al. report a prospective, multi-institutional phase II trial evaluating R0 resection rates in patients with R-PDAC and BR-PDAC who received neoadjuvant gemcitabine/nab-paclitaxel (GnP) and stereotactic body radiotherapy (SBRT), with secondary outcomes including safety and overall survival. A total of 49 patients with PDAC from five academic institutions initiated neoadjuvant therapy. Of these, 14/20 R-PDAC and 16/29 BR-PDAC patients completed all planned chemotherapy and SBRT. Subsequently, 12 (60%) R-PDAC and 11 (38%) BR-PDAC patients underwent resection. The trial demonstrated that 9/29 (31%) individuals with BR-PDAC achieved R0 resection after neoadjuvant therapy and surgery, sufficient to meet the predefined target for this group. However, only 9/20 (45%) R-PDAC patients achieved R0 resection, failing to meet the other primary objective. Adjuvant chemotherapy was initiated in 4 R-PDAC and 7 BR-PDAC resected patients, with completion rates of 75% (3/4) and 57.1% (4/7), respectively. Regarding safety, 44/49 patients experienced at least one grade 3 or greater toxicity, with eight patients (four per cohort) hospitalized for adverse events.

Despite anatomically favorable disease, only ~55% of R-PDAC patients proceeded to surgery, with fewer than half achieving R0 resection. This finding underscores the biologic heterogeneity of R-PDAC and the limitations of anatomic staging alone (7). Similarly, only 38% of BR-PDAC patients underwent resection. Current definitions of resectability, which are used for surgical planning, rely solely on anatomic criteria. However, this approach overlooks disease biology, which substantially influences outcomes. This limitation is highlighted by the high rate of early recurrence observed in many patients (as high as 65.6%) (8). Collectively, these data suggest that anatomic features alone are insufficient to predict which patients will benefit most from resection. In contrast, studies have suggested that R0 resection feasibility is closely related to tumor biology. The presence of certain tumor gene alterations has been found to predict lower R0 resection rates, increased tumor aggressiveness and margin positivity (9). Other work has linked high stromal fibroblast content and associated immune infiltration (e.g., CD8⁺ and dendritic cells), with higher R0 rates. Together, these studies support a broader understanding that R0 achievement reflects a complex interplay of preoperative therapy response and intrinsic tumor biology. They also emphasize the need to incorporate tumor biology into assessments of resectability and expected outcomes (10).

Another contributor to the relatively low proportion of patients who ultimately underwent resection was the interval around delivery of SBRT. Only 29% of patients with R-PDAC and 50% of patients with BR-PDAC who completed neoadjuvant chemotherapy made it to operative exploration. These are twice the dropout rates observed during neoadjuvant chemotherapy. Reported reasons for SBRT discontinuation included disease progression and treatment withdrawal, among others. However, the criteria used to define disease progression were not clearly specified and could have varied across institutions. Although SBRT is generally a well-tolerated treatment, the time it takes to deliver this therapy delays surgery. The fact that disease progression accounts for a significant portion of dropout during this phase raises concern for potential selection bias whereby tumors with more indolent tumor biology (slower growth) are more likely to reach surgery, which can confound outcomes. Smaller sample sizes themselves can also skew median values and influence conclusions. Caution should be undertaken when allocating time to therapies like SBRT, a modality without a demonstrated overall survival benefit, particularly in patients who might otherwise have been candidates for timely operative resection. As research into tumor biology advances, targeted therapies such as immunotherapy are likely to play an increasingly important role in the preoperative management of pancreatic cancer, potentially supplanting modalities like SBRT.

One limitation acknowledged is that FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan and oxaliplatin) has become standard neoadjuvant therapy, when tolerable, since the trial’s inception, reducing generalizability in the current landscape (11). However, this also highlights the rapid evolution of what is considered “standard” in the field of pancreatic cancer. In fact, new data have emerged interrogating the efficacy of FOLFIRINOX in the neoadjuvant setting. While FOLFIRINOX remains superior in the adjuvant setting (11), emerging neoadjuvant data, including from the PREOPANC-2 trial, show no significant overall survival difference compared with gemcitabine-based approaches in R-PDAC and BR-PDAC (12). These data demonstrate the persistent uncertainty about optimal treatment regimens, particularly for R-PDAC. An additional limitation is the lack of carbohydrate antigen 19-9 (CA 19-9) analysis, which is often used in the clinical decision-making of neoadjuvant chemotherapy versus upfront surgery in patients with R-PDAC. Preoperative CA 19-9 has been consistently linked to survival outcomes, resection completion, and potentially margin status post-neoadjuvant therapy (13-15). Stratifying or comparing CA 19-9 between cohorts could provide further insight into margin outcomes.

The role and composition of neoadjuvant therapy in R-PDAC remains an active topic of debate. The phase II trial by Cohen and colleagues offers a valuable snapshot of the challenges inherent in treating localized PDAC with neoadjuvant GnP and SBRT. While the regimen was feasible and achieved meaningful R0 resection rates in a subset of patients with borderline resectable disease, the notably low rates of surgical exploration and margin-negative resection in anatomically resectable disease highlight the limitations of relying solely on anatomic criteria for treatment decisions. Additionally, only 14% of originally eligible participants completed all prescribed courses of therapy, highlighting the substantial toxicity of current regimens and the dominant influence of tumor biology over anatomic staging in determining outcomes. Looking ahead, chemotherapy selection is expected to increasingly incorporate tumor biology, not only for predicting treatment response but also for guiding regimen choice. Recent data from the PASS-01 trial (in metastatic PDAC) compared modified FOLFIRINOX and GnP, stratified by RNA subtype (classical vs. basal-like) from pretreatment biopsies (16). Overall trends favored GnP, with particularly pronounced differences observed in the classical subtype. These studies underscore the potential of molecular profiling to guide personalized regimen selection and predict R0 likelihood and resectability, moving beyond imaging alone for treatment decisions.

The field of cancer care is evolving rapidly, with much of the current research focused on developing personalized and targeted therapies. Recent studies have identified tumor-specific molecular and genetic markers that can predict preoperative lymph node involvement and treatment efficacy using modern tools such as next-generation DNA sequencing and artificial intelligence (17,18). Ultimately, studies like Cohen’s highlight the need for more prospective multi-institutional collaboration and investigation, ideally incorporating modern chemotherapy regimens, biomarker stratification and robust assessment of biologic predictors, to refine perioperative strategies and improve long-term survival for patients with this devastating disease.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Pancreatic Cancer. The article has undergone external peer review.

Peer Review File: Available at https://apc.amegroups.com/article/view/10.21037/apc-26-0012/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apc.amegroups.com/article/view/10.21037/apc-26-0012/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.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Koti S, Standring O, Vithlani N, et al. Trends and Outcomes of Neoadjuvant Chemotherapy for Clinical Stage T1 Pancreatic Cancer. J Surg Oncol 2025;131:646-57. [Crossref] [PubMed]
2. Habib JR, Kinny-Köster B, Bou-Samra P, et al. Surgical Decision-Making in Pancreatic Ductal Adenocarcinoma: Modeling Prognosis Following Pancreatectomy in the Era of Induction and Neoadjuvant Chemotherapy. Ann Surg 2023;277:151-8. [Crossref] [PubMed]
3. Javed AA, Habib JR, Andel PCM, et al. Implications of Neoadjuvant Therapy on Prognostic Factors in Pancreatic Ductal Adenocarcinoma: A Path Towards Personalized Prognostication. Ann Surg 2025; Epub ahead of print. [Crossref]
4. NCCN Guidelines for Patients: Pancreatic Cancer. (2025). Available online: https://www.nccn.org/patients/guidelines/content/PDF/pancreatic-patient.pdf
5. Springfeld C, Hackert T, Palmer DH, et al. New implications from long-term outcomes of perioperative therapy in resectable pancreatic cancer. Br J Cancer 2026;134:531-42. [Crossref] [PubMed]
6. Cohen DJ, Goldberg JD, Leichman L, et al. Perioperative therapy for resectable and borderline resectable pancreatic adenocarcinoma: an Academic Gastrointestinal Cancer Consortium Study. Oncologist 2025;30:oyaf271. [Crossref] [PubMed]
7. Rompen IF, Habib JR, Wolfgang CL, et al. Anatomical and Biological Considerations to Determine Resectability in Pancreatic Cancer. Cancers (Basel) 2024;16:489. [Crossref] [PubMed]
8. Jones RP, Psarelli EE, Jackson R, et al. Patterns of Recurrence After Resection of Pancreatic Ductal Adenocarcinoma: A Secondary Analysis of the ESPAC-4 Randomized Adjuvant Chemotherapy Trial. JAMA Surg 2019;154:1038-48. [Crossref] [PubMed]
9. Oshi M, Tokumaru Y, Patel A, et al. A Novel Four-Gene Score to Predict Pathologically Complete (R0) Resection and Survival in Pancreatic Cancer. Cancers (Basel) 2020;12:3635. [Crossref] [PubMed]
10. Katsuta E, Rashid OM, Takabe K. Fibroblasts as a Biological Marker for Curative Resection in Pancreatic Ductal Adenocarcinoma. Int J Mol Sci 2020;21:3890. [Crossref] [PubMed]
11. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817-25. [Crossref] [PubMed]
12. 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]
13. Distler M, Pilarsky E, Kersting S, et al. Preoperative CEA and CA 19-9 are prognostic markers for survival after curative resection for ductal adenocarcinoma of the pancreas - a retrospective tumor marker prognostic study. Int J Surg 2013;11:1067-72. [Crossref] [PubMed]
14. Katz MH, Varadhachary GR, Fleming JB, et al. Serum CA 19-9 as a marker of resectability and survival in patients with potentially resectable pancreatic cancer treated with neoadjuvant chemoradiation. Ann Surg Oncol 2010;17:1794-801. [Crossref] [PubMed]
15. Chavan N, Pande P, Desai G, et al. Predictive value of elevated CA 19-9 for positive resection margins after pancreaticoduodenectomy for pancreatic tumors. HPB (Oxford) 2021;23:S68.
16. 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]
17. Ouyang W, Peng Q, Lai Z, et al. Synergistic role of activated CD4(+) memory T cells and CXCL13 in augmenting cancer immunotherapy efficacy. Heliyon 2024;10:e27151. [Crossref] [PubMed]
18. Yu Y, Ouyang W, Huang Y, et al. Artificial intelligence-based multi-modal multi-tasks analysis reveals tumor molecular heterogeneity, predicts preoperative lymph node metastasis and prognosis in papillary thyroid carcinoma: a retrospective study. Int J Surg 2025;111:839-56. [Crossref] [PubMed]