Peri-operative radiotherapy for pancreatic ductal adenocarcinoma: current evidence and future directions: a narrative review

Introduction

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most challenging malignancies to treat, with high mortality and high recurrence rates even after surgical resection (1). While surgery offers the only potential cure, the introduction of multi-agent chemotherapy, particularly modified FOLFIRINOX (mFOLFIRINOX), has shifted the treatment paradigm toward neoadjuvant systemic therapy. This shift has reframed how peri-operative radiotherapy (RT) should be considered. The central question in current practice is whether RT provides additional clinical benefit when increasingly effective systemic therapy is already delivered (2-5).

Recent randomised trials including A021501 and PREOPANC-2 were specifically designed to address this issue, yet they have reached different conclusions. Contemporary guidelines also diverge; while earlier American Society of Clinical Oncology (ASCO) guidelines support adjuvant chemoradiotherapy (CRT) in selected high-risk patients, the 2023 European Society for Medical Oncology (ESMO) Clinical Practice Guideline advises against its routine use. These opposing positions illustrate the ongoing uncertainty surrounding the integration of RT into neoadjuvant systemic therapy for resectable and borderline-resectable PDAC (6-8). This review evaluates the rationale, evidence, and evolving role of RT in the perioperative setting within this modern treatment framework. We present this article in accordance with the Narrative Review reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-25-98/rc).

Methods

We conducted a narrative review of the literature addressing the role of perioperative RT in the management of PDAC. A Non-systematic literature review was conducted using PubMed and Google Scholar for English-language articles published between January 2000 and May 2025. The search terms included: “pancreatic cancer”, “pancreatic ductal adenocarcinoma”, “radiotherapy”, “chemoradiotherapy”, “SBRT”, “neoadjuvant”, and “adjuvant”. Additional relevant studies were identified through manual review of bibliographies from key publications. Relevant ongoing clinical trials and conference abstracts were also included where appropriate to highlight recent developments in the field.

Priority was given to randomised controlled trials, meta-analyses, international guidelines, and large retrospective studies, though selected observational studies were included to provide context. Studies were excluded if they were case reports, non-English, or without sufficient relevance to perioperative RT in PDAC. A summary of the search strategy is presented in Table 1.

Findings

Rationale for perioperative RT in pancreatic cancer

Biological behavior and patterns of spread

PDAC is an aggressive malignancy characterized by early local invasion, perineural spread, and high rates of systemic dissemination (9). Even in cases classified as anatomically resectable on imaging, pathologic evaluation after surgery frequently identifies extensive disease beyond the pancreas with adjacent vasculature involvement in 60–90% of cases (10). Additionally, perineural invasion is nearly universal and contributes to high locoregional failure rates following resection (11). Standard imaging modalities often underestimate true tumor extent, which complicates surgical planning and contributes to the high incidence of positive resection margins (R1) reported in up to 60% of cases (12). Recent studies further highlight the biological and clinical heterogeneity of PDAC, including variability in immune signatures, uncommon metastatic patterns, long-term survival trends in the FOLFIRINOX era, and outcomes following progression on modern systemic therapy (13-15).

Challenges in achieving R0 resection and local control

Despite advancements in surgical techniques, achieving an R0 resection remains challenging due to the propensity for PDAC to infiltrate along neural and vascular planes. This infiltrative behavior confers significant risk of local recurrence, particularly in patients with positive margins or nodal involvement. While distant metastases represent the predominant pattern of relapse accounting for 30–55%, locoregional recurrences also occur in approximately 30–50%, with isolated locoregional recurrence in 25–30% of patients (16-18). Data from PRODIGE 24 suggest that median survival following locoregional-first recurrence is poor and comparable to median survival for those who experience distant metastasis-first recurrence, 18.5 months for local-only, 14 months for distant-only, and 11.4 months for combined local and distant recurrence (19). Similar findings were seen in the ESPAC-4 trial with comparably poor median OS for both locoregional-first recurrence and distant metastasis-first recurrence (10). These findings highlight the importance of effective local and distant control measures. In the context of improved systemic options, RT remains a valuable adjunct aimed at optimizing local control and enhancing resection quality in selected patients.

Role and timing of RT

The role of perioperative RT in PDAC continues to evolve. Adjuvant RT may be considered in patients, particularly when preoperative therapy was not administered. In contrast, neoadjuvant RT, typically administered in the form of chemoradiation or stereotactic body radiation therapy (SBRT), may allow for greater downstaging, improved R0 resection rates, and earlier treatment of micrometastatic disease. The optimal sequencing of RT with systemic therapy, as well as the ideal radiation dose and fractionation, remain areas of active investigation. Guidelines consistently emphasize that these decisions must be made within an individualized, multidisciplinary tumor board.

Adjuvant radiation therapy: revisiting an evolving role

Historical controversies and limitations of early trials

The role of adjuvant RT in PDAC has long been controversial. Several early randomised trials, including ESPAC-1 and EORTC 40891, failed to demonstrate a clear overall survival (OS) benefit from the addition of CRT to surgery (20,21). These results led to a prolonged period of skepticism regarding the benefit of adjuvant RT. However, these trials had design flaws that limited the interpretation of their findings. For example, ESPAC-1 suffered from protocol heterogeneity and background RT in non-RT arms, while EORTC 40891 included a high proportion of periampullary tumors, which generally carry a better prognosis than PDAC.

Reappraisal in the modern context and patient selection

Despite early criticisms, subsequent studies have offered more nuanced insights into the potential role of adjuvant RT. The GITSG 9173 trial, while foundational, predates modern systemic therapy, but demonstrated improved OS with CRT compared to observation. The Pancreatic Cancer Meta-analysis Group which identified five randomised trials of adjuvant treatment and pooled individual patient data from four of them (875 patients), found no OS benefit from adjuvant CRT (median survival was 15 months with or without CRT), but suggested a potential role in patients with positive surgical margins (4).

More recently, the phase II/III NRG/RTOG 0848 trial evaluated adjuvant CRT following gemcitabine-based chemotherapy in patients with resected PDAC. After initial chemotherapy, 354 patients were randomised to receive CRT (50.4 Gy in 28 fractions with capecitabine) vs. observation. In the overall cohort (74% node-positive, 83% R0), CRT improved disease-free survival (DFS) (16 vs. 12 months) but did not significantly improve OS (31 vs. 27 months). However, in node-negative patients, CRT was associated with improved 5-year OS (48% vs. 29%) and DFS (47% vs. 19%) (22). These findings support the concept of selective benefit in well-defined patient subgroups, and likely those who have been selected for having a lower competing risk of distant metastasis and comparatively higher risk of locoregionally predominant disease.

Guideline endorsements and future perspectives

Contemporary guidelines reflect this evolving understanding. The 2019 ASCO guidelines recommend six months of adjuvant chemotherapy for all patients who did not receive neoadjuvant therapy (23). They also support consideration of adjuvant CRT in patients with high-risk pathologic features including positive surgery margin or nodal involvement.

Even in the era of intensified systemic therapy, such as mFOLFIRINOX, approximately half of progression events include a locoregional component (19). This underlines the ongoing relevance of adjuvant RT for improving local control, particularly in high-risk patients.

Additionally, emerging data from RTOG 0848 suggest that adjuvant CRT may offer survival benefit in node-negative patients, reinforcing the need for an individualised, risk-adapted approach. As neoadjuvant modern systemic therapy gains traction, the role of postoperative RT is likely to become increasingly tailored based on individual patient factors and surgical pathology.

A unifying explanation for these selective results is the concept of competing risks, whereby the relative contribution of locoregional versus systemic failure determines whether local therapy escalation can influence survival. In PDAC, distant metastasis is the dominant competing event. Thus, in patients with high systemic-risk biology, local therapy may have a lesser influence on OS, even when it improves local control. The node-negative subset benefit in RTOG 0848 illustrates this principle: when metastatic risk is lower, locoregional failure becomes clinically relevant, and RT exerts a measurable survival effect. Incorporating this framework helps contextualize why historical trials produced conflicting results and supports a risk-adapted approach to adjuvant CRT.

Preoperative radiation therapy in pancreatic cancer

Rationale and evolving trends

Preoperative therapy has become an increasingly adopted strategy in the management of PDAC, particularly for borderline resectable and select resectable cases (12). The rationale for preoperative RT includes optimizing local control, increasing R0 resection rates, delivering systemic therapy earlier to manage occult distant metastasis, and assisting with patient selection for subsequent oncologic resection by allowing a test of time and disease biology (24). Data show that even in seemingly resectable cases, up to 40–60% may ultimately have R1 resection, and postoperative therapy completion is suboptimal in many patients (10). Thus, delivering treatment preoperatively may ensure a greater proportion of patients receive multimodal therapy, potentially improving their outcomes.

Outcomes and evidence for neoadjuvant RT

Evidence supporting the integration of RT into neoadjuvant therapy for patients with resectable or borderline resectable PDAC comes from multiple retrospective studies, phase II trials, and emerging prospective data (Table 2). Randomised trials such as PREOPANC-1 and a study by Jang et al. have demonstrated that neoadjuvant CRT improves R0 resection rates, DFS and OS compared to upfront surgery (25,26). In PREOPANC-1, R0 resection increased from 43% to 72%, with improved DFS (8.1 vs. 7.7 months), and 5-year OS (21% vs. 7%), while Jang et al. reported a median OS of 21 vs. 12 months and R0 resection of 52% vs. 26% favoring the neoadjuvant arm (25,26). Another 4-arm randomised phase II trial (ESPAC-5) demonstrated that neoadjuvant therapy (chemotherapy or CRT) was associated with improved survival compared with immediate surgery, and preoperative CRT was associated with highest rates of R0 resection and pathologically negative lymph nodes (27). One-year OS was highest in the FOLFIRINOX (84%) and CRT (60%) arms compared to 39% with upfront surgery, suggesting independent effect of CRT upon OS. Similarly, studies from MD Anderson and the Alliance cooperative group (A021101) highlighted improved outcomes in borderline resectable disease using total neoadjuvant therapy (TNT) including radiation (28,29). Several meta-analyses have suggested that while neoadjuvant treatment may reduce resection rates overall, it improves R0 resection and lymph node negativity rates and potentially leads to better long-term survival (30-33).

Contemporary considerations and controversies

Contemporary discussions focus on the added value of preoperative RT in patients who have already received upfront systemic therapy such as mFOLFIRINOX (34,35). In parallel, efforts continue to refine optimal sequencing, radiation dose and fractionation, and patient selection. Hypofractionated RT regimens, SBRT, and proton therapy are under investigation for improving treatment precision while minimizing toxicity. Despite advances, the role of RT remains controversial in resectable PDAC, particularly in the context of highly active systemic regimens such as mFOLFIRINOX. Notably, the Alliance A021501 trial failed to show benefit from SBRT (33–40 Gy in 5 fractions) after FOLFIRINOX in borderline resectable disease (7). However, interpretation of these findings should be considered in light of several limitations, including the timing of randomisation, potential imbalances between treatment arms, and reduced statistical power following early closure of RT arm. As such, the study may be underpowered to draw definitive conclusions about the utility of preoperative RT, and caution is warranted in drawing broad conclusions from these findings (36). Beyond the methodological considerations, A021501 also highlights a key biological concept: after intensive induction mFOLFIRINOX, the majority of disease failures remain systemic. Under these circumstances, local therapy, whether SBRT or CRT, has limited potential to improve survival in an unselected population. In other words, the lack of benefit observed in A021501 may reflect persistent metastatic-dominant biology rather than ineffectiveness of RT. This aligns with the competing-risk model and underscores the importance of identifying patients in whom locoregional control is most meaningful.

PREOPANC-2 is a phase III randomised superiority trial that compared neoadjuvant FOLFIRINOX vs. gemcitabine-based neoadjuvant RT and adjuvant gemcitabine. The results indicated no difference between the two regimens in terms of OS and R0 resection rates (8). Although FOLFIRINOX was anticipated to demonstrate superior efficacy, CRT achieved comparable outcomes despite incorporating a less intensive systemic regimen, suggesting a potential independent influence of CRT on OS. This observation is particularly noteworthy given that the CRT arm received postoperative gemcitabine, which has been shown to be inferior to FOLFIRINOX in the adjuvant setting as illustrated in the PRODIGE-24 trial.

These findings are further supported by the preliminary results of PANDAS-PRODIGE 44, which evaluated mFOLFIRINOX with or without the addition of CRT. While the R0 resection rates did not differ significantly between the two arms, patients who underwent oncologic resection following CRT experienced improved OS (37). Taken together, these data reinforce the rationale for combining effective systemic therapy with RT, given their distinct mechanisms of action and complementary roles in addressing both locoregional and distant disease progression. When these data are interpreted collectively, a consistent pattern emerges: perioperative RT appears most valuable in patients whose disease biology or chemotherapy response places them at lower systemic risk. In such patients, the competing risk of early distant metastasis is diminished, and improvements in locoregional control may translate into survival benefit. Conversely, in patients with biologically aggressive disease despite chemotherapy, the marginal value of RT becomes small. This biologic and response-based stratification provides a coherent explanation for the divergent outcomes observed across neoadjuvant RT trials.

Technological advances in perioperative RT for PDAC

SBRT in the neoadjuvant setting

The use of SBRT in the neoadjuvant management of PDAC has attracted increasing research interest due to its ability to deliver highly conformal, ablative radiation doses over a short treatment course. SBRT offers logistical advantages—including reduced treatment time and minimal delays to systemic therapy—making it an attractive option in the perioperative window, particularly for patients with borderline resectable disease.

SBRT has been incorporated into TNT in PDAC (38). Retrospective studies have reported improved rates of R0 resection, nodal clearance, and local control when SBRT is used after induction chemotherapy. However, prospective data remain limited and mixed. The Alliance A021501 trial is the most notable phase II study evaluating preoperative SBRT in borderline resectable PDAC (7). Patients received eight cycles of FOLFIRINOX followed by randomisation to either surgery or SBRT (33 Gy in five fractions) prior to surgery. The SBRT arm was closed early due to futility, with no improvement in OS, raising questions about the routine use of SBRT in this setting.

A recent propensity-score matched analysis by Yun et al. found that neoadjuvant RT following chemotherapy in borderline resectable PDAC improved 2-year postoperative survival (77.2% vs. 66.9%, P=0.045) and R0 resection rates (92.8% vs. 81.9%, P=0.062) compared to chemotherapy alone. Most patients (90.7%) received SBRT (50 Gy in 5 fractions), with the remainder receiving CRT (56 Gy in 28 fractions). Surgery within 4 weeks of RT completion was associated with lower blood loss (450 vs. 850 mL, P=0.019) and reduced clinically relevant pancreatic fistulas (3.6% vs. 16.7%, P=0.056) (39).

While these findings have led to more cautious interpretation for preoperative SBRT, selected patients particularly those with borderline resectable tumors involving vascular structures may still benefit. Retrospective institutional experiences, such as those from MD Anderson, have reported high rates of R0 resection and encouraging local control with SBRT as part of a TNT approach. Nevertheless, SBRT in the preoperative setting remains investigational, and ongoing trials (e.g., MASTERPLAN, PANDAS-PRODIGE 44) are expected to further clarify its role (40,41).

Image-guided and adaptive RT techniques

Technological advances in image guidance and motion management are increasingly relevant in the perioperative setting, where precise targeting is essential to avoid damage to adjacent gastrointestinal organs and major vessels. Modern intensity-modulated radiation therapy (IMRT) and image-guided RT (IGRT) platforms have enabled more conformal treatment with reduced toxicity compared to historical techniques (42).

More recently, magnetic resonance-guided radiotherapy (MRgRT) has emerged as a promising tool. MRgRT allows for daily adaptive planning and real-time visualization of soft tissues, enabling more accurate treatment in tumors abutting or encasing critical luminal structures (43). Although most MRgRT data currently pertain to unresectable PDAC, its integration into neoadjuvant protocols is an area of active research. A recent phase II trial (NCT03621644) evaluated MR-guided adaptive SBRT (SMART) delivering 50 Gy in 5 fractions (BED =100) in patients with borderline resectable (43%) and locally advanced (57%) PDAC after induction chemotherapy. With a median follow-up of 14.2 months post-SMART, the 2-year OS was 40.5%, and late grade ≥3 GI toxicity was ≤4.6%. Approximately 35% of patients underwent surgery post-SMART. These results suggest SMART is a feasible and well-tolerated strategy warranting further investigation (44).

Target volume delineation and planning strategies

Accurate target volume definition is an integral part of effective perioperative RT in PDAC, given the tumor’s complex anatomical relationships and tendency for perineural and vascular invasion. Representative imaging for a patient with borderline resectable PDAC is shown in Figure 1.

Figure 1 Representative images for a patient with borderline resectable PDAC of the pancreas head including axial and coronal images at baseline (A,B) and post-chemotherapy (C,D). Baseline imaging demonstrated a 4.3 cm mass involving the gastric antrum and proximal duodenum with associated porta-hepatis and peri-pancreatic lymphadenopathy. Arterial involvement included <180° involvement of the common hepatic artery and venous involvement included >180° involvement of the portal vein, <180° involvement of the splenic vein, and <180° involvement of the superior mesenteric vein but extending distally to the level of initial draining veins. PDAC, pancreatic ductal adenocarcinoma.

Newer contouring atlases, such as the 2024 NRG atlas, recommend elective coverage of key neural and vascular pathways based on patterns of progression, further supporting the rationale for RT in this setting (45). High-risk clinical target volumes (CTVs) consistently included the gross tumor, involved nodes, abutting vasculature (celiac axis, SMA, SMV, portal, and splenic vessels), and areas of hazy peripancreatic soft tissue likely to harbor microscopic disease. Elective low-risk CTVs extended superiorly from the celiac take-off to the first jejunal branch of the SMA, encompassing regions of perineural and perivascular spread. While most participants endorsed a lower-dose elective volume, variation existed in coverage of the porta hepatis and cranial extent for tail lesions. A corresponding RT plan for the same patient is shown in Figure 2, demonstrating the CTVs and dose distribution.

Figure 2 Representative images of a radiotherapy plan for the patient described in Figure 1. (A,B) The CTV included a CTV4200 cGy encompassing the gross pancreatic tumor with 0.5–1 cm margin, involved lymph nodes with 0–0.5 cm margin, and adjacent tumor vessel interface (shown in cyan) and an elective CTV3750 (magenta) encompassing adjacent high risk elective nodal and peri-neural tracks including the pancreaticoduodenal, common hepatic, porta hepatis, celiac, superior mesenteric, and retroperitoneal regions. The distal extent of CTV3750 encompassed the first jejunal branches of the superior mesenteric artery and extended 1 cm beyond gross disease along the superior mesenteric vein. (C,D) The radiation dose distribution with the associated planning target volumes PTV4200 (magenta) and PTV3750 (orange). CTV, clinical target volume.

In terms of planning strategies, the field has moved beyond conventional three-dimensional conformal radiotherapy (3D-CRT). IMRT and volumetric arc therapy (VMAT) now predominate, offering superior conformality, improved organ-at-risk sparing (particularly of the duodenum, stomach and bowel), and potential for dose escalation. IMRT has demonstrated reduced acute gastrointestinal toxicity compared to the historical 3D-CRT cohorts (46,47). Proton therapy has shown dosimetric advantages in reducing low and medium dose exposure to luminal structures (48). However, clinical data remain mixed, and proton therapy carries unique challenges including range uncertainties and increased risk of toxicity at beam’s distal edge (48). Current non-randomised studies have not consistently demonstrated superior outcomes over photon-based RT.

As planning becomes increasingly individualized, the integration of MR-guided and adaptive RT, use of proton therapy in selected patients, and standardized contouring practices represent key advances aimed at improving local control while minimizing perioperative risk.

Limitations and future directions

This review is limited by its narrative design, which does not incorporate the methodological rigor of a systematic review or meta-analysis. As a result, while the synthesis highlights central themes across landmark and contemporary trials, it remains vulnerable to high risk of selection bias and the possibility of overemphasizing certain findings.

Nevertheless, the integration of advanced RT techniques into perioperative care for PDAC holds significant potential but requires continued investigation. As systemic therapy regimens improve and total neoadjuvant approaches become more common, there is increasing interest in using RT to maximize local control without compromising surgical outcomes.

Emerging evidence suggests that a risk-adapted strategy, rather than uniform application of perioperative RT, may optimize outcomes. Potential tools for biologic or treatment-response stratification include radiographic and biochemical response to induction therapy, ctDNA clearance dynamics, and baseline features associated with lower systemic risk, such as node-negative status. Integrated TNT approaches that combine effective systemic therapy with tailored locoregional intensification in appropriately selected patients may represent the next phase of individualized PDAC care (49).

Key questions remain regarding optimal dose and fractionation, timing relative to surgery, and appropriate patient selection. Ongoing trials such as MASTERPLAN (evaluating the addition of SBRT to FOLFIRINOX in PDAC) and PANDAS-PRODIGE 44 (assessing the addition of CRT after FOLFIRINOX) will be instrumental in shaping future practice (40,41).

Conclusions

The role of perioperative RT in PDAC is best understood within a competing-risk framework in which the balance between systemic and locoregional risk determines the potential survival impact of local therapy. While early trials generated controversy regarding its benefit, more recent data support its use in selected patients. The integration of RT with modern systemic therapy and advanced planning techniques offers the potential to enhance local control and improve resection outcomes. As total neoadjuvant strategies become more established, the role of RT will likely continue to shift toward a more individualized approach. Ongoing trials will be key in defining its optimal use and refining patient selection.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Eric C. H. Lai) for the series “Carcinoma of Pancreas” published in Chinese Clinical Oncology. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-25-98/rc

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-25-98/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-25-98/coif). The series “Carcinoma of Pancreas” was commissioned by the editorial office without any funding or sponsorship. K.R.J. reports receiving editor honoraria from RadOncQuestions.com, LLC. The authors have no other 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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