Not so fast—should neoadjuvant chemotherapy be routine in resectable pancreatic cancers?

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with rising incidence and accounts for approximately 500,000 deaths worldwide each year (1). Even in non-metastatic disease with curative potential, prognosis remains poor despite adjuvant chemotherapy, with 5-year overall survival (OS) rates ranging from 15–30% for resectable or borderline resectable tumors (2,3). In borderline resectable disease, the Alliance A021501 and ESPAC5 trials provided evidence for using neoadjuvant combination chemotherapy to improve outcomes (4,5). For resectable disease, however, the role of neoadjuvant therapy has been more controversial as several trials failed to demonstrate significant survival benefit (6-8). Nevertheless, practice patterns have been shifting toward increasing use of neoadjuvant chemotherapy in resectable PDAC, particularly in cases with high-risk features as recommended in recent NCCN Guidelines (9). In April 2025, Unno et al. reported the results from the Prep-02/JSAP05 study, the first randomized trial to demonstrate a significant survival benefit for neoadjuvant chemotherapy compared to upfront surgery in resectable PDAC (10).

The Prep-02/JSAP05 study was a phase II/III multi-center randomized trial conducted in Japan. A total of 364 patients with resectable and borderline-resectable (with portal vein contact) PDAC were randomized to either upfront surgery or two 21-day cycles of neoadjuvant chemotherapy with gemcitabine and S-1 (the NAC-GS arm) (10). Both arms received 6 months of adjuvant S-1 therapy after surgery. In the intention-to-treat analysis, neoadjuvant chemotherapy significantly extended the median OS from 26.6 months in the upfront surgery arm to 37.0 months in the NAC-GS arm (hazard ratio of 0.73). Median relapse-free survival was also significantly longer in the NAC-GS arm (14.3 vs. 11.3 months). These findings support the use of gemcitabine and S-1 prior to surgery to improve survival in resectable PDAC.

Strengths and limitations

This study has several key strengths. Prep-02/JSAP05 was a well-designed, prospective, multi-center trial that randomized patients prior to treatment initiation. This randomization approach reduced potential selection bias, which was a significant limitation in previous trials such as PRODIGE 24/CCTG PA6 (11,12). The study also included adequate representation of clinicopathologic features seen in patients with PDAC, and specifically demonstrated survival benefits in both resectable and borderline resectable disease. The extent of survival gains with neoadjuvant chemotherapy at 10.4 months and a 27% relative reduction in the risk of death were both statistically significant and clinically meaningful. Secondary endpoints further provided strong biological basis for this survival benefit, including lower rates of intraoperative unresectability due to distant metastases and lower recurrence rate in the liver (30% in NAC-GS vs. 48% in the upfront surgery arm). While both arms had similar resection rates at ~86–87%, the NAC-GS arm showed significantly fewer lymph-node positivity at resection (59.2% vs. 81.4%), and more favorable pathologic response (36% vs. 81.1% having 10% or lower tumor cell destruction). Notably, although 72.6% of the NAC-GS arm experienced grade 3 or 4 adverse events (data were not reported for the upfront surgery arm), this additional chemotherapy exposure did not lead to increased perioperative morbidity. The completion rates for adjuvant S-1 therapy were also similar in both arms at 62–63% with comparable mean dose intensity at 77–79%.

The major limitation of this trial lies in its generalizability. The trial cohort was entirely Japanese and S-1 is not approved or widely available outside of Asia, including in the United States. The study does not address whether a longer neoadjuvant duration or more intensive triplet regimen such as mFOLFIRINOX preoperatively may provide greater survival benefit in resectable PDAC. The mechanism of action of S-1 is most similar to that of capecitabine, yet gemcitabine plus capecitabine (GemCap) has not yet been evaluated in the neoadjuvant setting for this patient population. It is also challenging to compare adjuvant S-1 monotherapy with standard of care outside of Asia, which typically uses mFOLFIRINOX or GemCap as adjuvant regimens (11-15). Of note, the particular design of this trial to assess the additive benefit of neoadjuvant therapy without adjusting for total chemotherapy exposure also raises the question of potential overtreatment. In contrast, a common practice in borderline resectable PDAC is to distribute 6 months of mFOLFIRINOX peri-operatively (4). Finally, this study did not report on translational biomarkers [e.g., circulating tumor DNA (ctDNA), immune signatures] to elucidate mechanisms of efficacy or patient-reported outcomes to evaluate patient impact. As with many clinical trials, real-world outcomes may be more modest as the trial participants often have better physical fitness and higher adherence to treatment than the general patient population.

Clinical implications and future directions

This study establishes that even a brief course of neoadjuvant chemotherapy with gemcitabine and S-1 can significantly improve long-term survival among patients with resectable PDAC. However, the NAC-GS regimen is unlikely to be adopted in the Western countries due to drug availability. While GemCap could be a comparable alternative, its efficacy in the neoadjuvant setting has not been studied. A global randomized controlled trial comparing GemCap or other commonly used neoadjuvant regimens (e.g., mFOLFIRINOX, gemcitabine/nab-paclitaxel) to gemcitabine/S-1 would be an ideal next step. As the technology of ctDNA advances, future studies may also incorporate ctDNA to guide the duration of neoadjuvant therapy in resectable disease.

While historically there have been ethical concerns about neoadjuvant therapy leading to missed opportunities for curative resection, there is now growing evidence that neoadjuvant therapy may lead to improved survival by reducing the risk of occult metastases in patients with resectable PDAC. As seen in this study, more patients in the upfront surgery arm were deemed unresectable due to distant metastases at time of surgery compared to the NAC-GS arm. However, while neoadjuvant chemoradiation has a role in borderline resectable tumors, it will likely have a limited role in resectable disease (8). JASPAC-04 compared neoadjuvant chemoradiation with S-1 to neoadjuvant gemcitabine plus S-1 and found a non-statistically significant trend towards improved survival favoring NAC-GS (16).

Finally, this study achieved what NORPACT-1 could not: proving a survival benefit with neoadjuvant combination chemotherapy. NORPACT-1 compared neoadjuvant FOLFIRINOX to upfront surgery for resectable pancreatic cancers but failed to show survival benefit with neoadjuvant FOLFIRINOX (6). In fact, the median OS in the FOLFIRINOX arm was lower at 25.1 months compared to 38.5 months in the upfront surgery arm, with a trend in higher adverse events as well. The better adherence and tolerability of S-1 in this study may help explain the contrasting result with NORPACT-1, where only 61% of patients completed all four cycles of neoadjuvant FOLFIRINOX and only about 50% of patients completed the planned adjuvant chemotherapy. These findings suggest that the lack of benefit seen in NORPACT-1 is more likely due to the intensity and completion rates of chemotherapy rather than a failure of the neoadjuvant approach in resectable disease.

Conclusion

Prep-02/JSAP05 is the first randomized phase III trial to demonstrate a clear survival benefit for neoadjuvant combination chemotherapy in resectable PDAC. The study findings address an important clinical gap in the management of early-stage pancreatic cancer and will shift the practice landscape towards a more systemic approach peri-operatively. We look forward to seeing the 5-year OS data and real-world outcomes with longer-term follow-up once this practice becomes more widely adopted in Asia. A similar trial in the United States or other Western countries would be invaluable, perhaps one with evolving standard of care (e.g., FOLFIRINOX), biomarker-driven endpoints and/or assessing quality of life impact on patients, in shaping future standards for preoperative management of resectable pancreatic cancers.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-25-89/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-25-89/coif). D.M. reports receiving grants or contracts from Acepodia, Actuate Therapeutics, ADC Therapeutics, Amgen, AVEO, Bayer, Blueprint Medicines, BMS, BioNTech, Dialectic Therapeutics, Epizyme, Fujifilm, ImmuneSensor, Immune-Onc Therapeutics, Leap Therapeutics, Lycera Corp, Merck, Millennium, MiNA Alpha, NGM Biopharmaceuticals, Novartis, Oncolytics, Orano Med, Puma, Qurient, Rafael, Repare Therapeutics, Triumvira Immunologics, Vigeo Therapeutics, and Warewolf Therapeutics; consulting fees from Actuate, Qurient, Lilly, Exelixis, Eisai; and payment or honoraria from Amgen, BMS, Eisai, and Exelixis; support for attending meetings and/or travel from Biontech; and participation on a Data Safety Monitoring Board or Advisory Board for Actuate Therapeutics. The other author has 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/.

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