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

Despite advances in multimodal therapy, pancreatic ductal adenocarcinoma (PDAC) remains a highly fatal tumor. For surgically resectable and borderline-resectable PDAC (BR-PDAC), the optimal integration of neoadjuvant chemotherapy and radiotherapy has yet to be established. Recent randomized studies (e.g., ESPAC-5F, NORPACT-1, Alliance A021501, and PREOPANC) and updated guidelines [of the National Comprehensive Cancer Network (NCCN), European Society for Medical Oncology (ESMO), and Japanese Society of Hepato‑Biliary‑Pancreatic Surgery (JASPAC)] now identify which patients are likely to benefit from treatment before surgery. For resectable PDAC, upfront surgery followed by adjuvant chemotherapy (typically modified FOLFIRINOX) remains the standard of care. However, new research (e.g., Prep-02/JSAP05) suggests that some high-risk patients may benefit from neoadjuvant therapy. For BR-PDAC, neoadjuvant multiagent chemotherapy (typically FOLFIRINOX) is widely accepted as the standard approach for increasing the likelihood of margin-negative resection and improving survival. Induction chemotherapy (with or without ablative radiotherapy) is commonly employed to downstage tumors in locally advanced PDAC. Debate continues as to the role of radiotherapy [either conventional chemoradiotherapy or stereotactic body radiotherapy (SBRT)]. PREOPANC reported a slight survival benefit for preoperative gemcitabine-based chemoradiotherapy in resectable PDAC and BR-PDAC, while Alliance A021501 reported no additional benefit from SBRT following FOLFIRINOX in BR-PDAC. Advanced imaging [multiphasic computed tomography/magnetic resonance imaging (CT/MRI) and positron emission tomography/computed tomography (PET/CT)] enhances the precision of staging and response evaluation. Molecular diagnostics, particularly germline/somatic BRCA and KRAS status and circulating tumor DNA (ctDNA) monitoring, are currently informing perioperative decisions and innovative therapeutics. As of 2025, personalized perioperative care guided by resectability status, tumor biology, and patient-specific characteristics has emerged as the key strategy for optimizing the selection of patients for neoadjuvant chemotherapy and/or radiotherapy. This review sought to synthesize the most recent evidence and guidelines on the treatment of resectable, BR, and locally advanced PDAC.