Neoadjuvant Treatment of Pancreatic Cancer

Curative therapy for pancreatic adenocarcinoma is only possible for patients who undergo complete surgical resection. However, given the locally invasive nature of pancreatic cancer, upfront surgery often results in positive surgical margins and leads to inferior survival compared with margin-negative resection. Neoadjuvant therapy can lead to primary tumor regression and has emerged as an alternative to upfront surgery and adjuvant therapy. This approach has the advantage of delivering cytotoxic therapy shortly after diagnosis, potentially producing primary tumor response and early treatment for microscopic metastatic disease. Moreover, it provides a period of observation to uncover aggressive tumor biology precluding curative surgery. Prospective, nonrandomized trials of neoadjuvant therapy in resectable pancreatic adenocarcinoma have been encouraging, with high rates of R0 resection and histologic evidence of treatment effect. These observations, coupled with the growing recognition of pancreatic tumors now defined as borderline resectable, have led to the expanded use of neoadjuvant therapy in patients with borderline resectable and locally advanced disease. Previous retrospective analyses from single institutions and larger, prospectively maintained data bases have consistently demonstrated the beneficial treatment effect of neoadjuvant therapy with meaningful downstaging. Recently, randomized trials comparing neoadjuvant therapy followed by surgery with upfront surgery and adjuvant therapy have confirmed the downstaging effect of various neoadjuvant therapy strategies. Some also demonstrate a survival advantage using neoadjuvant therapy, particularly in patients with borderline resectable disease. This chapter will briefly review the potential of neoadjuvant therapy to downstage resectable, borderline resectable, and locally advanced tumors, and delineate some challenges inherent in this approach. Surrogates of downstaging and treatment effect in neoadjuvant therapy will also be reviewed and future directions summarized.