Importance: It is estimated that pancreatic cancer (PC) will become the second leading cause of cancer-related death in the United States by 2030. Observations: Clinical and preclinical data support the understanding that PCmetastases occur early in the pathogenesis of this disease, even before the primary tumor can be detected. This has important implications for the clinical management of patients with localized PC, as surgery alone is unlikely to be curative for most patients. The delivery of postoperative adjuvant therapy is problematic in this disease because of themagnitude of the operation needed to remove the primary tumor, which can affect patient recovery and delay (sometimes indefinitely) the delivery of systemic therapy. For these reasons, the use of chemotherapy and/or chemoradiation prior to surgery (neoadjuvant therapy) is increasingly recognized as the preferred strategy for treatment sequencing. Neoadjuvant therapy is recommended for patients with borderline resectable PC and, at some centers, neoadjuvant therapy has been extended to patients with resectable PC aswell. Importantly, therapeutic advances in multidrug systemic therapy and radiation therapy have already been adopted in the neoadjuvant setting where treatment toxicity will not be compounded by surgical recovery. In addition, the use of localregional therapies in highly selected patients with locally advanced PC, following a prolonged period of induction systemic therapy, will be an area of intense scrutiny. Future improvements in diagnostic biomarkersmay allowfor real-time sequencing of multimodality therapy for individual patients based on a more accurate and timely assessment of treatment response. Conclusions and Relevance: Neoadjuvant treatment sequencing allows patients to receive multimodality therapy in a manner that prioritizes early exposure to systemic therapy to maximize the treatment of micrometastatic disease in an immune-competent host prior to surgical intervention. Patients who complete all intended neoadjuvant therapy, including surgery, experience an overall survival benefit that is unmatched by a surgery-first approach.
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