Background5-fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) is superior to gemcitabine in patients with metastatic pancreatic cancer who have a good performance status. We investigated this combination as neoadjuvant therapy for locally advanced pancreatic cancer (LAPC).MethodsIn this retrospective series, we included patients with unresectable LAPC who received neoadjuvant FOLFIRINOX with growth factor support. The primary analysis endpoint was R0 resection rate.ResultsEighteen treatment-naïve patients with unresectable or borderline resectable LAPC were treated with neoadjuvant FOLFIRINOX. The median age was 57.5 years and all had ECOG PS of 0 or 1. Eleven (61 %) had tumors in the head of the pancreas and 9 (50 %) had biliary stents placed prior to chemotherapy. A total of 146 cycles were administered with a median of 8 cycles (range 3-17) per patient. At maximum response or tolerability, 7 (39 %) were converted to resectability by radiological criteria; 5 had R0 resections, 1 had an R1 resection, and 1 had unresectable disease. Among the 11 patients who remained unresectable after FOLFIRINOX, 3 went on to have R0 resections after combined chemoradiotherapy, giving an overall R0 resection rate of 44 % (95 % CI 22–69 %). After a median follow-up of 13.4 months, the 1-year progression-free survival was 83 % (95 % CI 59-96 %) and the 1-year overall survival was 100 % (95 % CI 85-100 %). Grade 3/4 chemotherapy-related toxicities were neutropenia (22 %), neutropenic fever (17 %), thrombocytopenia (11 %), fatigue (11 %), and diarrhea (11 %). Common grade 1/2 toxicities were neutropenia (33 %), anemia (72 %), thrombocytopenia (44 %), fatigue (78 %), nausea (50 %), diarrhea (33 %) and neuropathy (33 %).ConclusionsFOLFIRINOX followed by chemoradiotherapy is feasible as neoadjuvant therapy in patients with unresectable LAPC. The R0 resection rate of 44 % in this population is promising. Further studies are warranted.

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Transforming growth factor ␤ 1 (TGF-␤ 1 )-inducible transcription factors have recently elicited interest because of their critical role in the regulation of cell proliferation, differentiation, and apoptosis. We have previously reported that the TGF-␤ 1 -inducible transcription factor, TIEG1, induces apoptosis in a pancreas-derived cell line. However, the mechanisms underlying the apoptotic effects of this transcription factor remain to be defined. In this study, using the TGF-␤ 1 -sensitive Hep 3B cell line, we have defined the mechanistic sequence of events that characterize TIEG1-mediated apoptosis and compared these events with the changes observed during TGF-␤ 1 -induced apoptosis. Both TGF-␤ 1 -and TIEG1-induced cell death were accompanied by an increase in the generation of reactive oxygen species and a loss of the mitochondrial membrane potential preceding the morphological changes of apoptosis. In contrast, increases in caspase 3-like activity and glutathione (GSH) depletion occurred later in the apoptotic process, concurrent with the morphological features of apoptosis. The antioxidant, trolox, decreased the formation of reactive oxygen species and apoptosis. These results demonstrate that similar to TGF-␤ 1 , TIEG1 induces apoptosis by a mechanism involving the formation of reactive oxygen species.

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