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Objective: Although the prognosis in patients with pancreatic adenocarcinoma remains poor, adjuvant gemcitabine plus S-1 chemotherapy (GEM + S-1) after surgical resection for pancreatic adenocarcinoma has been shown to improve survival. S-1 is a novel oral fluoropyrimidine combination including tegafur (a prodrug of 5-fluorouracil; 5-FU), dihydropyrimidine dehydrogenase (DPD) inhibitor (5-chloro-2,4-dihydroxypyrimidine), and orotate phosphoribosyltransferase (OPRT) inhibitor (potassium oxonate). To clarify the relationship between expression of intratumoral enzymes related to the metabolism of 5-FU and its derivatives and response to adjuvant chemotherapy with GEM + S-1 for pancreatic adenocarcinoma, we evaluated thymidylate synthase (TS), DPD, and OPRT expression immunohistochemically in resected pancreatic adenocarcinoma tissues. Methods: Polyclonal antibodies were used to immunostain sections of 106 formalin-fixed paraffin-embedded specimens of pancreatic adenocarcinoma resected between 1998 and 2009. The relationship between intratumoral TS, DPD, and OPRT expression and prognosis was evaluated statistically. Results: Out of 106 patients, 75 (70.1%) received adjuvant GEM + S-1 chemotherapy. High intratumoral TS, DPD, and OPRT expression was present in 68 (64.1%), 39 (36.8%), and 70 (66.0%) cases, respectively. Comparison of overall survival between High and Low intratumoral TS or OPRT expression revealed no significant difference regardless the application of adjuvant GEM + S-1 chemotherapy. In the GEM + S-1 (+) group, overall survival was significantly longer in the Low DPD subgroup than in the High DPD subgroup (hazard ratio [HR], 0.661: 95% confidence interval [CI], 0.447 - 0.978; P = 0.031), whereas in the GEM + S-1 (-) group, there was no significant difference between the High DPD and Low DPD subgroups. Moreover, in the High DPD group, there was no significant difference in overall survival between the GEM + S-1 (+) and GEM + S-1 (-) subgroups, whereas in the Low DPD group overall survival was significantly higher in the GEM + S-1 (+) subgroup by univariate analysis (HR, 0.456; 95% CI, 0.295 - 0.683; P < 0.001). Conclusion: Low intratumoral DPD expression was associated with increased overall survival in patients with pancreatic adenocarcinoma who received adjuvant GEM + S-1 chemotherapy. DPD is a relevant predictive marker of benefit from adjuvant GEM + S-1 chemotherapy in patients with resected pancreatic adenocarcinoma.