Perioperative therapy for resectable and borderline resectable pancreatic adenocarcinoma: interpreting the AGICC study

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. Even in the small proportion of patients where surgery with curative intent is deemed feasible, most will relapse within 2 years (1,2). For this reason, systemic therapy must accompany surgery where possible. However, how best to deliver this remains up for debate. Against this background, Cohen and colleagues report the Academic Gastrointestinal Cancer Consortium (AGICC) multicentre, single-arm phase II study of a perioperative strategy comprising three cycles of gemcitabine plus nab-paclitaxel (GEM/ABRAX), stereotactic body radiotherapy (SBRT) (33 Gy in five fractions), surgery, and then post-operative GEM/ABRAX (three further cycles).

The study’s central message is that although AGICC met its pre-specified benchmark for borderline resectable PDAC (BR-PDAC), the study was small and non-comparative, and therefore cannot support strong conclusions regarding efficacy in either BR-PDAC or resectable PDAC (R-PDAC). It is best interpreted as a feasibility-oriented perioperative study rather than a standard-setting trial (3).

Why perioperative therapy is an attractive approach and why it often fails

The logic behind giving systemic therapy before surgery is to treat micrometastatic disease when patients are typically most fit. Furthermore, it provides a prognostic indicator because early progression during neoadjuvant therapy (NAT) identifies those least likely to benefit from morbid surgery as well as improving the probability of achieving margin-negative resection. A further argument supporting NAT is that a substantial proportion of patients do not receive or complete the intended adjuvant chemotherapy after pancreatic resection, largely due to postoperative complications and recovery delays. Large observational datasets consistently show that omission of adjuvant chemotherapy is common and is associated with postoperative morbidity (4,5).

However, the proportion of patients successfully downstaged by various neoadjuvant therapies is low (approximately 25–30%) (6-8). This is not necessarily the failure of NAT as a concept but more a reflection of the challenges faced in assessing outcomes due to variable staging definitions, differences in surgical technique and vascular resection thresholds, inconsistent pathology processing, regimen tolerability, and perhaps most importantly the biological heterogeneity among patients labelled “resectable”. When trials are interpreted only looking at the patients who undergo surgery, they risk embedding favourable selection of patients whose disease did not progress and who remained fit enough for surgery and therefore overstating efficacy and failing to show where the pathway truly fails. These factors are particularly important in small single-arm studies.

What the AGICC trial contributes

AGICC is informative as it highlights the real-world feasibility issues of a complex perioperative programme. Among 86 consented patients, only 49 ultimately initiated protocol therapy (R-PDAC n=20; BR-PDAC n=29) emphasising the importance of evaluating perioperative strategies on an intention-to-treat basis rather than by post-resection endpoints alone (3). This pre-treatment attrition serves as a reminder that perioperative programmes must be judged by intention-to-treat deliverability rather than by post-resection endpoints alone. A regimen that appears promising among those who complete treatment may still fail to improve population-level outcomes if it cannot be delivered consistently across the pathway.

SBRT was an additional selection pressure with approximately one in eight treated patients unable to proceed to SBRT because of planning constraints such as proximity to stomach or small bowel. In practical terms this reinforces that SBRT is not universally deliverable, even in experienced centres. Furthermore, mandatory SBRT may introduce selection bias as patients excluded from SBRT may have anatomically more challenging tumours and removing them may distort resection and margin outcomes in small single-arm cohorts.

The reported outcomes similarly require cautious interpretation. AGICC did not meet the R-PDAC R0 benchmark (45% R0) and did meet the BR-PDAC R0 benchmark (31% R0) (3). Median overall survival (OS) was 19.5 months in R-PDAC and 15.7 months in BR-PDAC, with a treated-population median OS of 19.4 months (3). These figures, particularly in the resectable cohort, argue against any overly optimistic reading of perioperative intensification in anatomically resectable disease. Toxicity was also considerable, including high rates of grade ≥3 adverse events and an on-treatment sepsis death in the BR-PDAC cohort (3). Combining these findings supports the cautious interpretation that AGICC demonstrates that a multi-component perioperative approach can be delivered in a subset of patients, while highlighting that loss of participants and toxicity can quickly take away any theoretical advantages.

Interpreting “R0” rates and more informative endpoints

The low R0 rate in R-PDAC is striking, but margin status after NAT should be interpreted with caution. In PDAC, R0 definitions vary, some centres defining R0 as no tumour at the inked margin (0 mm), while others use the “1-mm rule”. In the AGICC trial, R1 was defined as microscopic tumour within 1 mm of any margin. The UK Royal College of Pathologists notes the ongoing controversy and describes how different clearance thresholds (0 vs. 1 mm) are used in practice (9). This variability limits direct comparison of single-arm R0 rates across studies unless pathology protocols are tightly standardised.

More fundamentally, R0 and other surrogate markers should not be overinterpreted as reliable predictors of OS in the neoadjuvant setting. OS remains the most clinically meaningful endpoint of perioperative PDAC treatments, and surrogate markers such as R0, pathological response, and treatment completion, while potentially informative are not a substitute (10,11). This is especially important when studies are small, non-comparative, or vulnerable to selection across multiple steps of the treatment pathway.

For this reason, perioperative strategies are better assessed with a more informative panel of endpoints including intention-to-treat survival, completion of planned systemic therapy, nodal downstaging, pathological response grading, CA19-9 kinetics, and patterns of relapse, e.g., local versus distant. These measures better reflect both systemic disease control and the real-world deliverability of the treatment regimen. Complete pathological response after NAT in PDAC is very uncommon. Although its occurrence may reflect marked treatment sensitivity, its rarity limits its utility as a practical endpoint, and it should not be viewed as a substitute for intention-to-treat OS when interpreting perioperative studies.

How AGICC fits within current evidence [2026]

Since the AGICC trial opened in 2016 treatments have changed. Adjuvant modified FOLFIRINOX (mFOLFIRINOX) became the reference standard for fit patients after PRODIGE 24, and neoadjuvant approaches became more widely adopted for BR-PDAC in many centres (12,13). However, interpretation of perioperative studies remains challenging, especially in the absence of appropriate standard-of-care control arms. In R-PDAC, giving chemotherapy before surgery is an appealing strategy, but a consistent survival advantage over immediate surgery followed by adjuvant treatment has yet to be proven (11).

Looking at R-PDAC, SWOG S1505 randomised patients to perioperative mFOLFIRINOX versus perioperative GEM/ABRAX and showed that perioperative multi-agent therapy is feasible in selected patients while illustrating the challenges of completion and the difficulty of improving outcomes in this setting. It should not be interpreted as demonstrating superiority, noninferiority, or equivalence of either regimen (14).

Similarly, PREOPANC-2 and PACT-21/CASSANDRA provide important contemporary context but do not resolve the question of the optimal perioperative regimen, nor do they justify indirect cross-trial conclusions about relative efficacy (15,16). PREOPANC-2 compared neoadjuvant FOLFIRINOX with gemcitabine-based chemoradiotherapy in resectable and BR-PDAC and did not show an OS difference between arms, underscoring how difficult it is to demonstrate survival superiority between credible perioperative strategies (15). PACT-21/CASSANDRA, which evaluated preoperative PAXG against mFOLFIRINOX in stage I–III resectable and BR-PDAC, suggests that alternative multi-agent regimens may also be active in this setting (16). Taken together, these studies reinforce the need for caution when drawing regimen-specific conclusions in the absence of an appropriate direct comparator. The limited gains across perioperative trials reinforce that regimen optimisation alone is unlikely to deliver transformative survival outcomes without parallel advances in biological selection and novel, mechanism-based combinations.

For BR-PDAC, the argument for NAT is stronger than for resectable disease, supported by trials including ESPAC-5 which showed an improved survival with short-course neoadjuvant chemotherapy (including FOLFIRINOX or gemcitabine/capecitabine) versus immediate surgery, despite similar resection rates (17). Alliance A021501 trialled neo-adjuvant mFOLFIRINOX with or without hypofractionated radiotherapy for BR-PDAC and did not support the routine addition of radiotherapy in that setting with the radiotherapy-containing arm closing early for an inadequate R0 resection rate (18). Likewise, the broader perioperative literature has not provided clear randomised evidence that radiotherapy improves OS when added to current systemic approaches in resectable or borderline R-PDAC (10,11).

Aligning with National Institute for Health and Care Excellence (NICE) and European Society for Medical Oncology (ESMO) in 2026

ESMO’s 2023 guideline endorses NAT as a standard consideration for BR-PDAC, typically multi-agent chemotherapy such as mFOLFIRINOX for fit patients and allows consideration of neoadjuvant strategies in R-PDAC with high-risk features, ideally within trials and high-volume centres (13). NICE guidance takes a more conservative stance, advising to only consider NAT for both borderline resectable and R-PDAC as part of a clinical trial (19). In practice, neoadjuvant approaches are commonly considered in BR-PDAC. Importantly, there is currently no prospectively validated practical definition of “high-risk” resectable disease that can be used routinely to guide perioperative treatment selection. Biological risk stratification is appealing in principle but remains an area for prospective study rather than current standard practice. Furthermore, the AGICC regimen is not immediately applicable in Europe and the UK. Although gemcitabine plus nab-paclitaxel is well established internationally, in Europe and the UK it is commissioned only for untreated metastatic PDAC. This means neoadjuvant use is off-label and cannot be routinely used outside of clinical trials (20,21).

What should clinicians and trialists take from AGICC now?

The key lesson from AGICC is that perioperative therapy is best understood as a pathway, not just a choice of drugs. Improving outcomes will require future studies focusing on regimen choice but also on intention-to-treat deliverability and the reasons patients fall off the pathway, standardised pathology workflows and margin reporting to improve comparability across studies (9), and OS.

In summary, AGICC does not establish perioperative gemcitabine/nab-paclitaxel plus SBRT as a new standard for resectable or BR-PDAC. It does, however, provide a useful real-world feasibility signal and a reminder of how attrition, toxicity, endpoint interpretation, and limited generalisability can complicate the translation of perioperative strategies into practice. There remains the need for future trials to be pragmatic, biomarker-informed, and designed around deliverability and completion.

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-26-0015/prf

Funding: This work was supported by the CRUK City of London Centre Award (CTRQQR-2021\100004).

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://apc.amegroups.com/article/view/10.21037/apc-26-0015/coif). The authors have no conflicts of interest to declare.

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