Pancreatic adenocarcinoma: treating a systemic disease with systemic therapy

Pancreatic adenocarcinoma, even when resectable, remains highly lethal. Although surgical outcomes have improved considerably, median overall survival after surgery and adjuvant therapy such as single-agent gemcitabine remains less than 2 years. We discuss preclinical and clinical data supporting the contention that even early-stage pancreatic cancer is a systemic disease. Autopsy series reveal that 70% to 85% of patients die of systemic recurrence, rather than local disease, after pancreatic cancer resection. Preclinical studies using genomics and mouse models reveal evidence of metastatic spread even before histopathologic evidence of a pancreatic tumor. Analogous to breast cancer, we propose that the Halstedian approach of treating pancreatic cancer as a local, surgical problem should be replaced by Fisher's alternative hypothesis of cancer as a systemic disease. Newer multiagent chemotherapy regimens have shown meaningful response rates and improvement in overall survival in the metastatic setting and, for the first time, offer investigators an opportunity to use effective systemic therapy. We emphasize that a surgery-first approach is not resonant with our current understanding of pancreatic adenocarcinoma biology and that an upfront systemic approach for even resectable pancreatic cancer warrants testing in clinical trials.