Parenthetically, the issue at hand is whether we can select our patients better so as to (I) identify patients with strictly borderline/locally advanced non-metastatic disease a priori and treat them with chemoradiation therapy and (II) intensify

this local therapy in those patients who are likely to have local tumor progression as the predominant source of disease-related mortality? Improvements in imaging techniques Inhibitors,research,lifescience,medical have significantly enhanced our ability to identify the extent of locoregional disease in the pancreas and stratify pancreatic cancer into potentially resectable, borderline resectable, and locally advanced. Nevertheless, accurate identification of metastatic disease remains a challenge because of the frequent occurrence of occult metastatic deposits in the liver and peritoneum that are not readily visualized non-invasively by current imaging Inhibitors,research,lifescience,medical technology. We and others have addressed this therapeutic dilemma by using induction chemotherapy to either treat micrometastatic disease or give occult metastatic disease an opportunity to manifest itself on subsequent imaging (7,8). By excluding patients with metastatic disease identified Inhibitors,research,lifescience,medical on repeat imaging after chemotherapy, the pool of patients who undergo consolidative chemoradiation therapy is

enriched with those who are most likely to have localized non-metastatic disease. Concentrating a localized treatment modality on these patients offers the possibility of these patients reaping the maximum benefit of standard chemoradiation therapy. With the advent of newer chemotherapeutic regimens with greater systemic efficacy like FOLFIRINOX and gemcitabine-abraxane, this sequencing of chemotherapy followed Inhibitors,research,lifescience,medical by chemoradiation

therapy may further select patients for maximum benefit from chemoradiation therapy. The next challenge is to further select these patients for intensification of local therapy with a focal radiation boost in those patients predicted to have Inhibitors,research,lifescience,medical a pattern of failure where local relapse is the dominant site of recurrence. Indeed, there is converging evidence that, contrary to the pathway signaling widespread perception that all patients with pancreatic cancer die as a result of distant metastatic disease, complications of local tumor progression are a product information significant source of disease-related mortality. Selecting these patients for intensified radiation therapy is therefore a viable therapeutic strategy if a biomarker of local-dominant biology can be identified and validated. A recent Batimastat autopsy study of pancreatic cancer patients noted that intact Smad4 expression in tumors predicts for a predominantly loco-regional failure pattern (9). This correlation was also observed in locally advanced pancreatic cancer patients treated with chemotherapy followed by chemoradiation therapy (10). This provides a rationale for potentially personalizing and intensifying radiation therapy via a focal boost in patients with intact Smad4.