Pancreatic adenocarcinoma: new strategies for success.

Pancreatic adenocarcinoma ranks as the most challenging of human malignancies, with overall 5-year survivorship being measured in a couple of percent. Major progress has occurred regarding the molecular underpinnings and pathogenesis of pancreatic adenocarcinoma, definition of the epidemiology and genetics of this disease, identification of individuals at risk, and in 2008, the preliminary description of the pancreatic genome. However, clinical developments over the past decade have been modest and incremental at most. The core drug and the backbone of treatment in all settings of pancreatic adenocarcinoma- adjuvant, locally advanced, and metastatic-remains gemcitabine. The past decade of research focused initially on combining cytotoxic therapies with gemcitabine, and more recently, on combining newer "targeted agents." Some success has been observed by combining the platinum analogs and the fluoropyrimidines with gemcitabine in the advanced pancreatic cancer setting. Three- and four-drug combinations have also been assessed, but the data are limited and the major trade-off becomes a toxicity-benefit equation. In relative terms, more limited incremental gains have been observed by combining erlotinib with gemcitabine, while other randomized phase III trials of targeted agents combined with gemcitabine have essentially shown no benefit. Several of the newer generation anti-vascular agents (VEGF-trap, axitinib) are being evaluated in ongoing phase III trials. In the short-term, expectations for advances in pancreatic adenocarcinoma therapy are reserved, with most progress likely to be made in therapy refinement and patient selection. However, it is reasonable to surmise that major progress will evolve as the molecular biology of pancreatic adenocarcinoma continues to be unraveled, as the infrastructure for translational research is strengthened with new preclinical models, and with recognition of the prerequisite requirement for intensive cross-disciplinary collaboration.