Neoadjuvant therapy for left-sided resectable pancreatic ductal adenocarcinoma: evidence-based shift or premature extrapolation?

Systemic adjuvant combination chemotherapy for six months either with modified (m) FOLFIRINOX (5-fluorouracil, folinic acid irinotecan, and oxaliplatin) or gemcitabine-capecitabine (GemCap) is well established as the standard of care for patients with resectable (EmR) pancreatic ductal adenocarcinoma (PDAC) (1-6). Short course neoadjuvant therapy is the preferred treatment for borderline resectable (EmBR) PDAC cancers rather than EmR cancers based on high quality evidence from randomized controlled trials (7-10). Most of these trials however are largely composed of patients with cancers in the head of the pancreas, rather than in the body and tail. In the ESPAC3 trial, which showed that adjuvant gemcitabine did not have longer survival than 5-fluorouracil/folinic acid, there were 43 total and 80 left sided (distal) pancreatectomies representing a nominal 123 (11.3%) body and tail cases from 1,088 patients randomized (3). In the ESPAC4 trial, which showed that adjuvant GemCap produced longer survival than gemcitabine monotherapy, there were 49 total and 60 left sided (distal) pancreatectomies representing a nominal 109 (14.9%) body and tail cases from 730 patients randomized (4,6). Neither of these body/tail pancreas PDAC groups was analyzed separately in terms of overall survival. Thus, there is a relative knowledge gap with respect to perioperative chemotherapy in this particular subset of pancreatic cancer.

A post hoc analysis of an international multicenter retrospective cohort of 1,236 patients who had distal pancreatectomy (2007–2015) from the European Consortium on Minimally Invasive Pancreatic Surgery (E-MIPS) group, identified 136 (11.0%) patients who received neoadjuvant chemotherapy for resectable and borderline resectable PDAC (EmR + EmBR) (11). In 94 of these patients matched 1:1 to patients undergoing upfront resection the median [95% confidence interval (CI)] overall survival was 27 (14–39) months (neoadjuvant group) versus 31 (19–42) months (upfront surgery) respectively (P=0.277) (11).

Another retrospective propensity-matched analysis of the USA National Cancer Database (2006–2015) identified 408 (9%) of 5,003 distal pancreatectomies that had neoadjuvant therapy, of whom 353 had 1:1 matching with upfront surgery patients (12). Chemotherapy dose intensity was not included in the matching. Adjuvant therapy was given to 246 (69.7%) patients in the neoadjuvant therapy group and to 125 (35.4%) patients in the upfront surgery group (P<0.001) (12). The median overall survival was 33.0 months in the neoadjuvant therapy group versus 27.0 months in the upfront surgery group (P=0.009) (12).

More recently a retrospective study has been reported by Rangelova et al. featuring registry information (2013–2019) that included data from the E-MIPS group along with data from the International Consortium on Advanced Pancreatic Surgery from centers in four different continents (13). The key finding was that patients receiving neoadjuvant chemotherapy before surgery followed by adjuvant chemotherapy had prolonged overall survival compared to patients having upfront surgery and adjuvant treatment (13). In this study 290 (13%) out of 2,282 patients with left-sided pancreatic resection had neoadjuvant chemotherapy (13). Neoadjuvant mFOLFIRINOX was used in 98 (38%) of patients and gemcitabine-nab-paclitaxel was used in 65 (22%) of patients, 97 (33%) also had radiotherapy (13). The median [interquartile range (IQR)] neoadjuvant treatment duration was 9 (5–16) weeks. Adjuvant chemotherapy was given to 1,427 (72%) of the 1,992 upfront surgery patients and to 209 (72%) patients in the neoadjuvant group. Single-agent adjuvant chemotherapy was given to 137 of 209 (66%) neoadjuvant patients compared to 1,050 of 1,428 (74%) patients in the upfront surgery group (P=0.016). Adjuvant mFOLFIRINOX was administered to 31 (15%) of 209 patients in the neoadjuvant therapy group compared to 88 (6%) of 1,428 patients after upfront surgery (P<0.0001) (13).

Following a median (IQR) follow-up of 61 (46–82) months 1,354 (59%) patients had died (13). In patients treated with neoadjuvant therapy the median (95% CI) overall survival was 49 (44–59) months with a 5-year (95% CI) overall survival of 42% (36–49%). In patients treated with upfront surgery the median (95% CI) overall survival was 38 (35–41) months with a 5-year (95% CI) overall survival of 36% (34–39%) (P=0.009) (13). Neoadjuvant therapy was associated with an adjusted median (95% CI) overall survival of 53 (43–64) months compared to 37 (35–39) months with upfront surgery (P=0.0003) and adjusted 5-year (95% CI) overall survival rates of 47% (41–52%) versus 35% (34–38%) respectively (P=0.0001) (13). The effect of neoadjuvant therapy was more pronounced in patients with a larger tumors and higher serum carbohydrate antigen 19-9 (CA19-9) levels, but not for patients with splenic artery, splenic vein, retroperitoneal, and multivisceral tumor involvement, indicating a major difference from pancreatic head cancers (13).

Cox regression in the multivariable model by continent also showed that Asia contributing 807 (35%) patients had the best survival with a hazard ratio (95% CI) of 0.66 (0.58–0.76), followed by the USA contributing 353 (15%) patients with a hazard ratio (95% CI) of 0.79 (0.67–0.92), compared to the referent Europe contributing 1,102 (48%) of the patients (P<0.0001) (13). χ² values and P values obtained from likelihood ratio tests for the full multivariable Cox regression model showed that the most powerful predictor of survival was diagnostic serum CA19-9 level, followed by geographical region, solid tumor size, and neoadjuvant therapy (13). This cohort has been very well analyzed but ultimately falls well short of the evidence required to change clinical practice for the following reasons:

• Governance and provenance of the data: there is no way of validating which patients were entered and which were not, and whether the data themselves are all accurate. There is a high risk of bias in this setting.
• Selection of neoadjuvant patients: the authors themselves recognize that this is a major basic flaw biasing the analysis in favor of this group. Patients were included only after they had resection. Thus, patients who progressed whilst receiving neoadjuvant therapy and did not have a successful resection were automatically excluded. They did not characterize the rate and causes of failure to reach surgery in those referred for neoadjuvant treatment such as biopsy related complications for tissue diagnosis required prior to chemotherapy but not before upfront surgery. Patients who had serious surgical complications including death also may not have been included. An internal quality measure would be to include all postoperative complications in both groups. A key element in the Kaplan-Meier survival curves shows a relatively higher early death rate in the adjuvant group than in the neoadjuvant group indicative most likely of biased patient inclusion.
• Chemotherapy dose intensities: these are missing which is highly important since total chemotherapy dosage is the principal determinant of overall survival (4,5).
• Combination versus single agent adjuvant chemotherapy: single agent adjuvant chemotherapy was more commonly used in the adjuvant therapy group which would have a negative biased effect on overall survival (1-6). Additionally, the neoadjuvant groups received the more active combination chemotherapies which now also have become standard in the adjuvant setting, but the adjuvant group did not.
• Year of data entry: to minimize bias the two groups should be proportionately matched in terms of the time period in which each patient was entered into the data base.
• Data inconsistencies: scientific hypotheses to be ‘true’ require both internal and external validation. After diagnostic serum CA19-9 levels, geographical region was the most powerful prognostic factor which was not adequately explained. Adjusted and unadjusted survival rates in the neoadjuvant group are surprisingly high, lacking other corroborative studies.

Thirty years ago, it was assumed that radiotherapy had to be given to all patients with pancreatic cancer. Now through well designed clinical trials we know that chemoradiation is not beneficial in terms of overall survival and may adversely alter the tumor microenvironment (TME) to be more resistant to treatment. Today there is also a strong band wagon that all patients undergoing surgery for PDAC must have neoadjuvant therapy. It should be appreciated however that different surgical stages of PDAC have differing TME transcriptomes that can be adversely affected by neoadjuvant chemotherapy and chemoradiotherapy (7,9). Hwang et al. showed recurrent expression programs in pancreatic cancer TME’s across malignant cells and cancer associated fibroblasts, including a neural-like progenitor malignant cell program that were enriched after chemotherapy and radiotherapy and associated with poor prognosis in independent patient cohorts (14). Zhou et al. in defining the impact of neoadjuvant chemotherapy on the TME using transcriptomic analysis combined with high-resolution mapping identified enrichment of characteristic persister cancer cells (15). Analysis of organoid models derived from these same post-chemotherapy samples demonstrated that these persister cells had detoxification pathways metabolizing the prodrug irinotecan, a constituent of mFOLFIRINOX (15). Enrichment of the PDAC TME with these persister cancer cells was associated with reduced overall survival in patients (15).

In contrast to pancreatic head cancers where there is a clear consensus on anatomical and biological (including CA19-9 levels) resectability criteria, there are no such consensus criteria for left sided cancers. Resectability features from baseline and neoadjuvant CA19-9 level responses appear to be shared between head and left sided cancers, but not vascular involvement. This major evidence and consensus gap needs to be closed. We agree with Rangelova et al. (13) in concluding that randomized controlled trials on neoadjuvant therapy specifically in patients with left-sided resectable (EmR) pancreatic cancers are needed not to “confirm” the role of neoadjuvant therapy but rather to better understand its effects on overall survival and tumor plasticity.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, HepatoBiliary Surgery and Nutrition. The article has undergone external peer review.

Peer Review File: Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-587/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-587/coif). C.S. declares advisory board membership for Astra Zeneca, Bayer, BMS, Roche, Incyte, MSD, Revolution Medicines, Servier and Taiho; travel support from Servia; honoraria for a lecture from Roche. J.P.N. declares that he has received grants from the Heidelberger Stiftung Chirurgie, Dietmar Hopp Stiftung GmbH, Bundesministerium für Bildung und Forschung and the Stiftung Deutsche Krebshilfe; consulting fees from Clarivate Analytics (UK) Limited, and ONO Pharmaceuticals; advisory board membership for BioNTech (BNT32); and the patent 52378-704.601 PCT 23 May 2025, Combination of Irinotecan and AP-001 for treating cancer. The other 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. Neoptolemos JP, Dunn JA, Stocken DD, et al. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet 2001;358:1576-85. [Crossref] [PubMed]
2. Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 2004;350:1200-10. [Crossref] [PubMed]
3. Neoptolemos JP, Stocken DD, Bassi C, et al. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA 2010;304:1073-81. [Crossref] [PubMed]
4. Neoptolemos JP, Palmer DH, Ghaneh P, et al. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet 2017;389:1011-24. [Crossref] [PubMed]
5. 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]
6. Palmer DH, Jackson R, Springfeld C, et al. Pancreatic Adenocarcinoma: Long-Term Outcomes of Adjuvant Therapy in the ESPAC4 Phase III Trial. J Clin Oncol 2025;43:1240-53. [Crossref] [PubMed]
7. Springfeld C, Ferrone CR, Katz MHG, et al. Neoadjuvant therapy for pancreatic cancer. Nat Rev Clin Oncol 2023;20:318-37. [Crossref] [PubMed]
8. Ghaneh P, Palmer D, Cicconi S, et al. Immediate surgery compared with short-course neoadjuvant gemcitabine plus capecitabine, FOLFIRINOX, or chemoradiotherapy in patients with borderline resectable pancreatic cancer (ESPAC5): a four-arm, multicentre, randomised, phase 2 trial. Lancet Gastroenterol Hepatol 2023;8:157-68. [Crossref] [PubMed]
9. Neoptolemos JP, Hu K, Bailey P, et al. Personalized Treatment In Localized Pancreatic Cancer. Eur Surg 2024;56:93-109.
10. 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]
11. Lof S, Korrel M, van Hilst J, et al. Impact of Neoadjuvant Therapy in Resected Pancreatic Ductal Adenocarcinoma of the Pancreatic Body or Tail on Surgical and Oncological Outcome: A Propensity-Score Matched Multicenter Study. Ann Surg Oncol 2020;27:1986-96. [Crossref] [PubMed]
12. Nassour I, Adam MA, Kowalsky S, et al. Neoadjuvant therapy versus upfront surgery for early-stage left-sided pancreatic adenocarcinoma: A propensity-matched analysis from a national cohort of distal pancreatectomies. J Surg Oncol 2021;123:245-51. [Crossref] [PubMed]
13. Rangelova E, Stoop TF, van Ramshorst TME, et al. The impact of neoadjuvant therapy in patients with left-sided resectable pancreatic cancer: an international multicenter study. Ann Oncol 2025;36:529-42. [Crossref] [PubMed]
14. Hwang WL, Jagadeesh KA, Guo JA, et al. Single-nucleus and spatial transcriptome profiling of pancreatic cancer identifies multicellular dynamics associated with neoadjuvant treatment. Nat Genet 2022;54:1178-91. [Crossref] [PubMed]
15. Zhou X, An J, Kurilov R, et al. Persister cell phenotypes contribute to poor patient outcomes after neoadjuvant chemotherapy in PDAC. Nat Cancer 2023;4:1362-81. [Crossref] [PubMed]