Perioperative pancreatic ductal adenocarcinoma care in 2025: who needs neoadjuvant?—who needs radiation?

Introduction

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers (1). Total surgical resection offers the only potential for cure; however, even with surgery, 5-year survival is only around 20–40% (2). Traditionally, the standard treatment approach for resectable PDAC consisted of pancreatectomy followed by chemotherapy (e.g., gemcitabine) based on important studies demonstrating a survival benefit. More recently, intensified adjuvant regimens, such as modified FOLFIRINOX, have greatly improved survival outcomes in fit patients. However, the risk of recurrence remains high, and only approximately half of patients complete adjuvant therapy (3). The proposed algorithm is illustrated in Figure 1.

Figure 1 Proposed perioperative management algorithm for PDAC in 2025. The algorithm begins with initial assessment and imaging, followed by stratification by resectability: (I) resectable tumors proceed to upfront surgery followed by adjuvant therapy; (II) borderline-resectable tumors receive neoadjuvant therapy, followed by re-assessment; if tumor downstaging has been achieved, surgery followed by adjuvant therapy is performed; otherwise, patients are managed as unresectable; (III) patients with unresectable tumors receive palliative chemotherapy or best supportive care. PDAC, pancreatic ductal adenocarcinoma.

Perioperative therapy, including neoadjuvant treatment before surgery, has become more popular. Neoadjuvant therapy can treat micrometastatic disease at an early stage, increase the probability of completing systemic therapy, and may even downstage malignancies. Neoadjuvant treatment is commonly used in borderline-resectable PDAC (BR-PDAC); however, debate continues as to its use in resectable PDAC. In locally advanced (unresectable) PDAC, induction therapy is commonly employed to achieve conversion to resectability in responsive patients (4).

This review addresses key questions in the current perioperative management of PDAC, including which patients should receive neoadjuvant chemotherapy, which patients should undergo upfront surgery, and when radiotherapy is necessary before or after surgery. It also examines the most recent randomized trials (e.g., ESPAC-5F, NORPACT-1, Alliance A021501, PREOPANC, and Prep-02/JSAP05) and guidelines [of the National Comprehensive Cancer Network (NCCN), European Society for Medical Oncology (ESMO), and Japanese Society of Hepato-Biliary-Pancreatic Surgery (JASPAC)] to delineate evidence-based interventions. It also discusses how imaging [computed tomography/magnetic resonance imaging/positron emission tomography (CT/MRI/PET)] and genetic profiling [BRCA, KRAS, and circulating tumor DNA (ctDNA)] have improved staging and aided clinicians in selecting optimal treatment strategies. Based on integrated current data, clinical decision-making algorithms are suggested and future directions for personalizing perioperative PDAC therapy are noted. The evidence reviewed in this manuscript is current through December 2025, with anticipated longer-term follow-up data in 2026 noted where relevant (5).

Definitions of resectability and relevant guidelines

PDAC is anatomically classified as resectable, BR, or locally advanced based on vascular involvement as assessed by high-quality imaging, typically contrast-enhanced pancreatic protocol CT and/or MRI. According to the NCCN criteria, resectable PDAC occurs when the tumor does not touch the celiac artery (CA) or superior mesenteric artery (SMA) and only touches the portal vein or superior mesenteric vein at an angle of less than 90° (6,7). In BR-PDAC, the tumor typically touches the SMA/CA at an angle of less than or equal to 180°, or touches more than one vein but may still be able to be repaired. Locally advanced (unresectable) PDAC is characterized by over 180°encasement of the SMA/CA or irreparable venous invasion (6). These categories help guide treatment decisions and estimate the likelihood of achieving complete (R0) resection.

The staging approach is reflected in the guidelines. In most cases of resectable PDAC, both the NCCN and ESMO guidelines recommend upfront surgery, followed by adjuvant multiagent chemotherapy (with FOLFIRINOX for fit patients) (6). Conversely, all major guidelines (including those of the NCCN, ESMO, and JASPAC) currently support neoadjuvant systemic therapy for BR-PDAC. For locally advanced PDAC, induction chemotherapy, (usually FOLFIRINOX or gemcitabine plus nab-paclitaxel) serves as the primary treatment. In selected cases, radiotherapy may be added to improve local disease control.

The JASPAC guidelines recommend neoadjuvant gemcitabine plus S-1 (an oral fluoropyrimidine) based on the PREP-02/JSAP05 trial (8,9). Conversely, Western facilities predominantly use FOLFIRINOX or gemcitabine plus nab-paclitaxel. It is important to note that the definitions of BR disease differ slightly among guidelines. The judgment of surgeons remains critical: in high-volume centers (≥20 pancreaticoduodenectomies per year), R0 resection may be achieved in patients with borderline vascular involvement using techniques such as arterial divestment or venous resection and reconstruction. Overall, current practice increasingly favors risk-adapted therapy; for example, high-risk resectable and BR tumors are often managed with neoadjuvant treatment, while very low-risk resectable PDAC cases often proceed directly to surgery (6,7).

Neoadjuvant therapy in resectable PDAC

Debate continues as to the role of neoadjuvant therapy in clearly resectable PDAC. Traditionally, patients with small tumors and no vascular involvement undergo upfront surgery. However, a substantial number of these patients experience early recurrence, likely due to the presence of micrometastases. Recent research is starting to shed light on this subject.

Resectable pancreatic cancer (RPC) has traditionally been treated with upfront surgery followed by adjuvant chemotherapy, based on evidence from trials supporting the use of adjuvant therapy, including the landmark CONKO-001 trial (7), and, more recently, PRODIGE-24, which demonstrated that adjuvant modified FOLFIRINOX significantly improved median overall survival (OS) compared with gemcitabine (54.4 vs. 35.0 months) (4). However, in an important Japanese phase II/III trial (Prep-02/JSAP05), patients with resectable PDAC were randomized to receive two cycles of neoadjuvant gemcitabine plus S-1 or upfront surgery. The preliminary results revealed a significant survival benefit in the neoadjuvant therapy arm (median OS: 37.0 vs. 26.6 months), and a hazard ratio (HR) favoring neoadjuvant therapy [HR 0.73, 95% confidence interval (CI): 0.56–0.95, P=0.018] (9). These findings suggest that even in anatomically resectable PDAC, neoadjuvant chemotherapy may improve outcomes if efficacious regimens are employed. Notably, both groups then received adjuvant chemotherapy (S-1 in Japan). The observed benefit was achieved within a pragmatic trial design. Thus, neoadjuvant therapy should be considered in patients with RPC capable of tolerating it (9).

More recently, the NCT03750669 trial compared sequential gemcitabine plus nab-paclitaxel followed by modified FOLFIRINOX with upfront surgery in resectable PDAC and reported improved event-free survival in the neoadjuvant therapy arm, further supporting a risk-adapted approach.

These inconsistent results underscore a critical observation: neoadjuvant therapy in resectable PDAC may confer a benefit in selected high-risk individuals [e.g., those with large tumors or increased carbohydrate antigen 19-9 (CA19-9) levels], but it has not yet been adopted as the standard of care for all patients. Meta-analyses of trials and institutional series indicate that neoadjuvant regimens may improve R0 rates and address micrometastatic disease without adversely affecting resection rates; however, significant improvements in OS have primarily been observed in patients with BR disease rather than in those with low-risk resectable disease (10). In contrast, the PRODIGE24 adjuvant trial and similar studies support upfront surgery followed by adjuvant chemotherapy as the prevailing protocol for low-risk RPC. Ongoing trials, such as Alliance A021806, a phase III study comparing perioperative therapy and adjuvant therapy in resectable PDAC, will further elucidate optimal treatment strategies.

Debate continues as to which patients with resectable PDAC should receive neoadjuvant therapy. In practice, many clinicians favor a neoadjuvant therapy approach for tumors that can be resected but exhibit high-risk features, including a large tumor size, borderline vascular contact, markedly elevated CA19-9 levels, or bulky nodal disease on imaging, based on the assumption that such patients may harbor micrometastases and may thus benefit from upfront systemic therapy. For genuinely low-risk RPC (e.g., small peripheral tumors with normal CA19-9 levels), urgent surgery remains a viable option in 2025, given the lack of definitive evidence regarding the benefits of neoadjuvant chemotherapy and the efficacy of contemporary adjuvant regimens (8,10).

Neoadjuvant therapy in BR-PDAC

BR-PDAC carries a significant risk of positive margins following upfront surgery. Numerous trials support neoadjuvant therapy as the standard of care for this patient population. The advantages include the early treatment of occult disease, tumor downstaging, and the selection of patients most likely to respond to surgery.

In the multicenter ESPAC-5F trial, 90 patients with BR-PDAC were randomized to one of four treatment strategies: urgent surgery, neoadjuvant therapy with gemcitabine plus capecitabine, FOLFIRINOX, or capecitabine-based chemoradiotherapy. The primary endpoint was 1-year OS. Neoadjuvant was associated with significantly higher 1-year OS rates (78% with gemcitabine plus capecitabine and 84% with FOLFIRINOX vs. 39% with urgent surgery; P=0.0028) (1). The patients who received neoadjuvant therapy also had high resection rates (approximately 55%), and higher R0 resection rates compared to those who received urgent surgery (23% vs. 14%) (11). While these findings were derived from a phase II investigation, the findings support the use of neoadjuvant therapy in BR-PDAC to improve survival outcomes.

In the Dutch PREOPANC trial, patients with resectable PDAC or BR-PDAC were randomized to receive neoadjuvant gemcitabine-based chemoradiotherapy or upfront surgery (12). At the 5-year follow-up, the neoadjuvant arm demonstrated improved OS (5-year OS 20.5% vs. 6.5%; HR 0.73, 95% CI: 0.56–0.96, P=0.025) (12). While the median OS gain was small (~15.7 vs. 14.3 months), the considerable improvement in long-term survival showed that preoperative therapy (i.e., the combination of gemcitabine plus chemoradiotherapy) had a long-lasting effect (12). The benefit was observed in both the resectable PDAC and BR-PDAC patients.

The Alliance A021501 trial examined neoadjuvant regimens in BR-PDAC. In this phase II study, patients were randomized to receive either eight cycles of modified FOLFIRINOX alone or seven cycles of modified FOLFIRINOX followed by stereotactic body radiotherapy (SBRT; 5 fractions) (11). The group that received SBRT demonstrated lower rates of margin-negative resection and significantly shorter OS (median OS 17.1 vs. 29.8 months). The trial was terminated early for futility, indicating that SBRT failed to demonstrate efficacy (11). Early termination may also raise the possibility of selection bias.

Biologically, PDAC has a high propensity for early systemic dissemination, and intensifying local therapy with SBRT may not improve outcomes when micrometastases are the primary driver of mortality. Evidence suggests that multiagent chemotherapy is highly effective in this setting, while the addition of short-course SBRT does not improve outcomes (and may even be associated with worse outcomes) (3). Presently, the standard treatment for BR-PDAC is neoadjuvant FOLFIRINOX (or similarly strong multiagent chemotherapy). Radiotherapy is generally only used in selected cases or clinical studies.

In summary, the data strongly support neoadjuvant systemic therapy for BR-PDAC. Due to its high response rate, FOLFIRINOX has become a preferred regimen in Western practice, while gemcitabine plus S-1 (GS) is preferred in Asia (13). Neoadjuvant treatment improves margin clearance and survival outcomes (14). Most guidelines currently recommend neoadjuvant chemotherapy for BR-PDAC. The use of radiotherapy (whether conventional or stereotactic) remains discretionary; it may be used in cases with substantial and persistent vascular involvement after chemotherapy, although its routine use has not demonstrated a clear additional benefit compared to chemotherapy alone (3).

Neoadjuvant therapy in locally advanced PDAC

By definition, locally advanced (unresectable) PDAC cannot be completely resected at the time of presentation. The standard approach is to use induction chemotherapy with the aim of achieving tumor downstaging. To date, no phase III trials have definitively demonstrated that induction chemotherapy achieves conversion to resectability. However, high-level regimens (e.g., FOLFIRINOX or gemcitabine plus nab-paclitaxel) have been shown to reduce tumor size and enable surgery in a subset of patients. Institutional evidence suggests that approximately 20–30% of carefully selected patients with locally advanced pancreatic cancer (LAPC) may achieve resectability following intensive treatment (8).

Due to the lack of randomized trials in LAPC, clinical practice relies on registry data and extrapolation from BR disease trials. At most centers, patients with LAPC receive systemic therapy, usually FOLFIRINOX, for at least 6 months (15). Surgical investigation is considered in patients with a favorable treatment response and good performance status. After four to six cycles of induction chemotherapy, restaging is performed. If tumors are downstaged to resectable or BR, surgical exploration is indicated. If tumors are stable but still unresectable, consolidative chemoradiotherapy or SBRT may be considered. For patients with progressive disease, second-line systemic therapy or enrollment in clinical trials is recommended.

Trials, such as Alliance A021101 (a phase II study of neoadjuvant FOLFIRINOX in BR-LAPC), have reported conversion rates exceeding 30%. Radiotherapy is frequently combined with systemic chemotherapy; some patients receive conventionally fractionated chemoradiotherapy after several months of chemotherapy, while others undergo SBRT. However, there is no agreement on the optimal use of radiotherapy in this setting, and the goal is to achieve local control and R0 resection. Notably, the Alliance A021501 trial (mentioned above) found that adding SBRT to FOLFIRINOX did not demonstrate any benefit in patients with BR disease (11). However, the applicability of these findings to patients with LAPC remains unclear. Some studies have shown that SBRT achieves good local control (approximately 80%), but its effect on survival remains unclear (6,7,15-17).

Radiotherapy in LAPC is tailored to each patient. Patients with unresectable tumors following chemotherapy may receive either high-dose SBRT (e.g., 5×6–8 Gy) or fractionated chemoradiotherapy to improve local control. Other patients may undergo surgery when feasible. Current research, including the Dutch PREOPANC-3 trial comparing total neoadjuvant FOLFIRINOX to FOLFIRINOX with radiotherapy in LAPC, will elucidate the role of radiotherapy in this context. In summary, neoadjuvant therapy in LAPC is administered with curative intent, with or without consolidative radiotherapy, and surgical resection should be considered in responders (4,15).

Role of radiotherapy in perioperative PDAC

The role of radiotherapy in PDAC remains controversial but continues to evolve. Chemoradiotherapy has not demonstrated a definitive OS benefit in the adjuvant setting and is not routinely incorporated into most Western treatment protocols, except in selected cases such as margin-positive (R1) resection. In the neoadjuvant setting, three distinct approaches are employed: (I) consolidative conventionally fractionated chemoradiotherapy (typically 50.4 Gy in 28 fractions with capecitabine or 5-FU), used in patients with persistent vascular involvement after induction chemotherapy; (II) SBRT (typically 3–5 fractions of 8–10 Gy each), offering shorter treatment duration and potential for local control; and (III) magnetic resonance (MR)-guided adaptive radiotherapy, which enables dose escalation (up to 50–60 Gy in 5 fractions) with improved sparing of at-risk organs.

The favorable results of the PREOPANC trial showed that gemcitabine-based chemoradiotherapy before surgery improved long-term survival compared to upfront surgery (18). However, that trial used an older regimen (gemcitabine with 36 Gy delivered over 6 weeks). In contrast, modern multiagent chemotherapy regimens (e.g., FOLFIRINOX) are more effective, raising the question of whether radiotherapy provides additional benefits in appropriately selected patients. The Alliance A021501 trial found that the addition of SBRT after FOLFIRINOX provided no benefit in BR disease, with worse outcomes observed in the SBRT arm (11). It may be that subclinical metastatic disease, rather than local recurrence, is the primary driver of mortality in most patients with PDAC; thus intensifying local therapy may be futile in the absence of effective systemic disease control.

Nevertheless, radiotherapy may be beneficial for specific patients. In cases where tumors remain BR after neoadjuvant chemotherapy (e.g., persistent vascular involvement), conventionally fractionated chemoradiotherapy may be used to improve margin clearance. SBRT has shown high rates of R0 resection with tolerable toxicity in some series (17). Ongoing trials, including RTOG 0848 (adjuvant chemoradiotherapy) and PREOPANC-3 (total neoadjuvant therapy in locally advanced PDAC), will help further define the optimal role of radiotherapy in this setting. In current practice, radiotherapy is not standard for all patients with PDAC but is considered selectively in BR or locally advanced disease to enhance local control, particularly in patients with a good response to chemotherapy but residual vascular involvement. Multidisciplinary discussion is essential to weigh potential benefits against gastrointestinal toxicity on an individual basis.

Clinical decision-making and treatment algorithms

In perioperative decision-making, treatment selection should take into account patient-related factors, tumor characteristics, and response to treatment. Factors supporting upfront surgery include small, peripherally located tumors without vascular involvement, low CA19-9 levels, and good performance status. It should be noted that in cases of marginal surgical eligibility, postponing surgery may jeopardize the opportunity for resection. Conversely, factors supporting neoadjuvant therapy include borderline vascular involvement, high CA19-9 levels, a tumors size greater than 4 cm, and clinical features suggestive of aggressive biology (16). Notably, the patient’s suitability for combination chemotherapy should also guide the selection of the treatment plan (e.g., FOLFIRINOX vs. gemcitabine-based therapy).

A simplified decision-making approach can be summarized as follows:

• Resectable PDAC: patients at low-risk may undergo upfront surgery followed by chemotherapy. Patients at high risk (e.g., those with a large tumor size, borderline anatomy, or elevated tumor markers) should undergo neoadjuvant chemotherapy (usually FOLFIRINOX or GS) (13).
• BR-PDAC: neoadjuvant multiagent chemotherapy is standard. Restaging is typically performed after approximately 4–6 months. If the tumor can be removed, surgery is performed. If the tumor remains on the edge, chemoradiotherapy or further chemotherapy may be considered on a trial basis.
• Locally advanced PDAC: the initial treatment consists of chemotherapy (e.g., FOLFIRINOX or gemcitabine plus nab-paclitaxel). If downstaging is achieved enabling resection, surgery is necessary; otherwise, consolidative chemoradiotherapy or SBRT may be considered for local disease control before surgery.

Advances in imaging perioperative planning

Accurate staging is very important. Contrast-enhanced CT with a specific pancreatic protocol is the best method for assessing vascular involvement. Supplementary multiphasic MRI may be used to detect small liver metastases or lesions not visible on CT (19). In one study, pancreatic MRI identified occult metastatic foci in patients with otherwise resectable cancer, leading to a change in treatment (2). Endoscopic ultrasound provides high-resolution imaging, facilitates biopsy, and is primarily used for tissue diagnosis. Fluorodeoxyglucose (FDG)-PET/CT is not commonly employed for primary staging according to guidelines; however, it may reveal distant metastases in ambiguous cases. The NCCN guidelines state that PET/CT should not replace CT/MRI, but it may be used if uncertainty remains (2). Researchers are currently exploring newer imaging methods, such diffusion-weighted MRI and PET/MRI.

During neoadjuvant therapy, serial imaging is used evaluate treatment response. Tumor size and vascular involvement should be reassessed after every 2–3 months of treatment. CA19-9 levels are also used; however, CA19-9 levels are not always reliable in patients who are Lewis antigen-negative or have biliary blockage (20). A decrease of less than 50% in CA19-9 after 2 months of neoadjuvant therapy is associated with poo-r outcomes and should prompt reconsideration of proceeding to surgery.

Radiomics is an increasingly used method; high-throughput extraction of imaging features may help predict treatment response (e.g., CT texture analysis is correlated with pathological response to neoadjuvant chemotherapy). These methods are still being tested, but may complement traditional imaging by 2025. Importantly, after neoadjuvant FOLFIRINOX, cross-sectional imaging may not reliably predict resectability. Therefore, surgical exploration should be considered in fit patients with a good performance status and a favorable biomarker response, even if imaging suggests persistent vascular involvement.

Molecular diagnostics and biomarkers

The biology of PDAC differs across patients. Molecular profiling is used in modern medicine to guide treatment selection when possible. All patients with PDAC should undergo germline and somatic testing for DNA repair mutations. Approximately 5–10% of patients with PDAC harbor hereditary BRCA1/2 or PALB2 mutations, and a further 5–10% demonstrate somatic homologous recombination deficiency (HRD). Patients with BRCA/HRD-altered malignancies may exhibit heightened sensitivity to platinum-based chemotherapy and poly(ADP-ribose)polymerase (PARP) medicines. The phase III POLO study showed that maintenance olaparib (a PARP inhibitor) significantly prolonged progression-free survival after first-line platinum treatment in patients with metastatic PDAC and germline BRCA mutations (21). Although the POLO study included patients with advanced cancer, it has increased interest in the earlier administration of PARP inhibitors. Ongoing trials are evaluating perioperative PARP inhibition in resectable PDAC patients with BRCA mutations (22).

KRAS mutations are present in most PDAC cases (approximately 90%); however, some KRAS mutations may represent new therapeutic targets. KRAS G12C mutations occur in approximately 1–2% of PDAC cases, and the G12C inhibitor sotorasib demonstrated limited efficacy in a phase I trial in PDAC (11). More broadly, novel KRAS G12D inhibitors, such as MRTX1133, are currently under investigation in early trials. Currently, KRAS mutational status has a limited effect on perioperative treatment planning. However, this may change as effective targeted therapies become available (23).

Other actionable mutations that are uncommon in PDAC include high microsatellite instability (MSI-H), neurotrophic tyrosine receptor kinase (NTRK) fusions, and human epidermal growth factor receptor 2 (HER2) amplifications. MSI-H tumors (<1% of PDAC) may benefit from immunotherapy (e.g., pembrolizumab); however, immunotherapy is not routinely used during surgery. Some centers nevertheless test for these mutations in patients with metastatic or BR disease (16).

ctDNA represents a promising new technique. Multiple studies have shown that the detection of KRAS-mutant ctDNA in plasma is correlated with outcomes. In resected PDAC, postoperative ctDNA has been shown to predict early recurrence with high sensitivity (≈90%) (24). For example, research has shown that patients with detectable ctDNA after surgery had a median recurrence-free survival of less than 6 months, whereas the ctDNA-negative patients experienced significantly prolonged remission (24). Consequently, ctDNA may help to stratify patients in the future (e.g., persistent postoperative ctDNA could help to identify which patients may benefit from more intensive treatment or enrollment in clinical trials).

Preoperative ctDNA positivity at diagnosis is also associated with worse outcomes. Although not yet part of standard practice, in the future, ctDNA testing may increasingly inform perioperative decision-making (e.g., therapy intensification in ctDNA-positive patients) (18). Post-neoadjuvant detectable ctDNA may guide surgical selection: patients with persistent ctDNA after 4–6 months of systemic therapy have a high risk of early recurrence and may benefit from continued systemic therapy or enrollment in clinical trials rather than immediate surgery.

Summary of biomarkers: key perioperative biomarkers include CA19-9 (prognostic, but non-specific), germline BRCA/HRD status, and ctDNA levels (24). Research on the tumor microenvironment, including immunotherapy targets, is ongoing but has yet to be integrated into routine practice for PDAC.

Future directions

The field of perioperative PDAC treatment is changing very quickly. Current trials and research initiatives include the following:

• Immunotherapy: checkpoint inhibitors have shown limited efficacy in PDAC, with the exception of MSI-H tumors. Novel methods, including vaccine-based treatments, combination chemo-immunotherapy approaches, and vaccines targeting KRAS mutations, are currently being evaluated in clinical studies. In perioperative trials, combinations of immunotherapy and neoadjuvant chemotherapy are under investigation.
• Personalized therapy: adaptive trial designs may change perioperative regimens based on early treatment response (e.g., modifying therapy midcourse in the absence of tumor downstaging). The use of circulating biomarkers (e.g., ctDNA and cfDNA methylation) to adjust therapy duration and intensity is an evolving field.
• Radiotherapy advances: MR-guided radiotherapy and proton therapy are two examples of new techniques that may allow higher doses of radiotherapy without damaging normal tissue. Studies are examining whether higher doses of SBRT (e.g., 5×10 Gy) can improve outcomes in borderline surgical candidates.
• Molecular targets: new targeted therapies, such as KRAS inhibitors and PARP inhibitors, are expected to be included in neoadjuvant regimens as they become available. Trials of neoadjuvant PARP inhibitors in BRCA-mutant PDAC and KRAS inhibitors in KRAS G12C PDAC are anticipated.
• Artificial intelligence and imaging: the application of machine learning to imaging datasets may improve prediction of which malignancies will respond best to treatment. Combining radiomic markers with clinical risk factors could aid in the selection of patients for neoadjuvant therapy.
• Global collaboration: large consortium studies, including the multinational ESPAC series and the Alliance/ASCO trials, are very important for obtaining high-quality evidence. By 2025, results from many ongoing trials (e.g., Alliance A021806, PREOPANC-3 and JCOG) will provide further insights into the neoadjuvant treatment paradigm.

Currently, multidisciplinary discussion remains essential. Surgeons, medical oncologists, radiotherapy oncologists, radiologists, and pathologists should collectively evaluate each patient’s condition and integrate all available information. It is essential to engage in shared decision-making with the patient, evaluating the potential advantages of neoadjuvant therapy (e.g., early treatment of micrometastases and improved R0 rates) against the associated risks (e.g., surgical delay and toxicity).

Conclusions

In 2025, tumor stage, tumor biology, and patient health all affect how PDAC is treated before, during, and after surgery. For resectable PDAC, the conventional treatment for most patients remains upfront surgery, followed by chemotherapy, with neoadjuvant chemotherapy reserved for patients with high-risk features. For BR-PDAC, neoadjuvant chemotherapy (ideally FOLFIRINOX or similar regimens) followed by re-assessment for surgery is the prevailing strategy, as this approach maximizes the chance of achieving a cure (4,7). Radiotherapy treatment is not standard practice, but is employed judiciously, including consolidative SBRT or chemoradiotherapy for non-responders to chemotherapy. It continues to be a focus of clinical trials. For locally advanced PDAC, aggressive induction chemotherapy is recommended, followed by re-evaluation and potential conversion to resectability. Radiotherapy may also be used for local disease control in selected cases.

Advances in imaging (e.g., high-resolution MRI and PET-based techniques) and molecular diagnostics (e.g., germline/somatic testing and ctDNA monitoring) are improving staging accuracy and enabling more individualized treatment strategies. By 2025, biomarker-driven and targeted approaches are expected to play an increasingly important role in perioperative decision-making. Due to high-quality data from recent and current trials, evidence-based decision-making is now more possible than ever before. The ultimate objective is to individualize perioperative therapy according to each patient’s risk profile, thereby improving long-term survival while minimizing superfluous treatment.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2026-0177/prf

Funding: This work was supported by the 2025 Qinghai Province Traditional Chinese (Tibetan) Medicine Development Project, titled “Evidence-based evaluation of the application effect of Tibetan bloodletting therapy in gout pain”, and the 2026 Qinghai Province Traditional Chinese (Tibetan) Medicine Research Project (No. ZD2026028), titled “Mechanism study of Tibetan medicine Shibawei Hezi Diuretic Pill in preventing diabetic gastroparesis by regulating intestinal GLP-1 secretion through the TGR5-mTOR signaling pathway”.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2026-0177/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/.

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(English Language Editor: L. Huleatt)