Pancreatic cancer: why is it so hard to treat?

No common malignancy is as rapidly and inevitably fatal as pancreatic ductal adenocarcinoma (PDA). This grim fact has driven substantial research efforts into this disease in recent decades. Unfortunately, the investment has yet to result in a meaningful increase in 5-year survival. This has prompted many pancreatic cancer researchers and advocates to redouble their efforts, but also requires one to step back and ask why the previous efforts were lacking and to consider why pancreatic cancer is so difficult to treat. The difficulties are legion. PDA is characterized by an insidious clinical syndrome, but is rarely diagnosed at a time when surgical resection is feasible. We lack markers of early detection and screening programs remain unproven even in high risk populations. The location of the tumor in the retroperitoneum, the advanced age of patients, and the systemic effects of disease limit the options for local therapy. Chemotherapy may provide a small benefit, but most efforts to improve on the current regimens consistently and stubbornly fail in advanced clinical trials. The molecular and cellular features of ductal pancreatic tumors are aggressive and underlay multiple levels of therapeutic resistance. Non-cell-autonomous features including stromal proliferation, reduced vascular density and immune suppression also contribute to therapeutic resistance. Growing awareness of these the fundamental features of PDA has begun to guide ongoing research efforts. Clinical trials are now specifically targeting these tumor properties and actively focusing on the therapeutic implications of tumor stroma. As reviewed here, reflecting on the fundamental question of why pancreatic cancer is so difficult to treat is a necessary and informative exercise that will aid our efforts to improve patient outcomes. These efforts will lead to improvements in clinical trial design, expand our focus to include the molecular and histologic implications of novel treatment paradigms, and ultimately change the lives of our patients.