Emerging therapeutic options for metastatic exocrine pancreatic cancer

Adenocarcinoma of the exocrine pancreas continues to challenge clinicians and investigators worldwide. The remarkable paucity of effective therapies has meant that the median survival of patients with metastatic disease has ranged from six months to a year at best. For years, gemcitabine has been the cornerstone of treatment, after it was shown to modestly improve survival and confer a significant clinical benefit when compared to fluorouracil. Since then, many attempts to build upon the gemcitabine backbone with the addition of a variety of cytotoxic and targeted agents have failed, with the notable exception of erlotinib; however, the magnitude of the improvement in survival with the addition of this agent to gemcitabine was small. Recently, FOLFIRINOX was established as a new standard of care for patients with an excellent performance status. This significant advance notwithstanding, there remains much room for improvement. Fortunately, we have gained considerable insights into the biology of pancreatic cancer in recent years, and many rational targets are currently being explored through a variety of approaches, including inhibition of signal transduction, modification of the tumor microenvironment, immunotherapy, tumor vaccine and gene therapy strategies. In this chapter, we begin by summarizing the currently accepted chemotherapeutic options for patients with metastatic disease. A discussion of investigational agents currently in various phases of clinical development, as well as those in the pipeline, along with the biologic rationale for each, then follows.