The role of systemic therapy in borderline resectable and locally advanced pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease, even in patients whose cancer is localized and non-metastatic. Surgical resection provides the only option for cure, but long-term survival rates remain dismal. For patients with borderline resectable (BR) disease who undergo upfront resection, many patients are either too unwell for subsequent adjuvant systemic therapy, develop recurrence soon after, or are found to have unresectable disease intra-operatively. There is increasing evidence for a neoadjuvant approach, using more conventional multi-agent chemotherapy regimens, which have demonstrated higher activity in the metastatic setting compared to single agents. For patients with locally advanced (LA) disease, which is unresectable by current definitions, there is mounting evidence that effective neoadjuvant systemic therapy is able to convert some patients' disease to a resectable state, offering the potential for long-term survival and cure. Herein we present a review of key trials focusing on prospective, randomized studies to provide high-level evidence supporting a neoadjuvant approach to both BR and LA PDAC. However, many knowledge gaps exist, such as the optimal neoadjuvant multi-agent chemotherapy regimen, the role of radiotherapy, and the safety and efficacy of adding immunotherapy to chemo/radiation therapy. Future challenges in determining the optimal approach to patients with BR or LA PDAC include not only overcoming the inherent difficulties in conducting complex, multidisciplinary, multicentre randomized trials in patients with a high-morbidity and mortality disease, but also trying to standardize disease definitions, treatment regimens, and outcome measures.