Treatment Response and Oncologic Outcomes Following Neoadjuvant Chemotherapy Switch in Localized Pancreatic Ductal Adenocarcinoma

BACKGROUND AND OBJECTIVES: Many patients undergoing neoadjuvant therapy for localized pancreatic ductal adenocarcinoma (PDAC) experience treatment intolerance or disease progression during initial therapy. Although chemotherapy switch is increasingly utilized, response rates and oncologic outcomes remain poorly defined. METHODS: Patients were identified from a prospectively maintained database of individuals undergoing neoadjuvant therapy for localized PDAC from 2012 to 2023. Eligible patients underwent chemotherapy switch between 5-fluorouracil and gemcitabine regimens with curative intent. Favorable response was defined as complete or partial radiographic response by RECIST, or stable disease with a ≥ 50% decline in CA 19-9 relative to levels before switch. Outcomes were measured from the date of chemotherapy switch. RESULTS: Out of 161 patients, 41% achieved favorable response. Body/tail, borderline resectable, and locally advanced disease were independently associated with nonfavorable response. Among favorable responders, 49% underwent resection versus 11% of nonresponders. Favorable response was independently associated with improved progression-free and overall survival, including among unresected patients. Overall, 47% derived meaningful oncologic benefit through favorable response, resection, or both. CONCLUSIONS: Chemotherapy switch offers a reasonable strategy in select patients with localized PDAC experiencing inadequate response or intolerance of initial therapy. This composite response framework identifies chemosensitive tumor biology, informs surgical decision-making, and stratifies prognosis.