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Objective: Although the prognosis in patients with bile duct cancer remains poor, adjuvant gemcitabine plus S-1 chemotherapy (GEM + S-1) after surgical resection for bile duct cancer 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 bile duct cancer, we evaluated thymidylate synthase (TS), DPD, and OPRT expression immunohistochemically in resected bile duct cancer tissues. Methods: Polyclonal antibodies were used to immunostain sections of 106 formalin-fixed paraffin-embedded specimens of bile duct cancer resected between 1989 and 2010. The relationship between intratumoral TS, DPD and OPRT expression and prognosis was evaluated statistically. Results: Out of 106 patients, 41 (38.7%) received adjuvant GEM + S-1 chemotherapy. High intratumoral TS, DPD and OPRT expression was present in 52 (49.1%), 39 (36.8%) and 57 (53.8%) cases, respectively. Comparison of overall survival between High and Low intratumoral DPD 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 TS subgroup than in the High TS subgroup (P = 0.015), whereas in the GEM + S-1 (-) group, there was no significant difference between the High TS and Low TS subgroups. Moreover, in the High TS group, there was no significant difference in overall survival between the GEM + S-1 (+) and GEM + S-1 (-) subgroups, whereas in the Low TS group overall survival was significantly higher in the GEM + S-1 (+) subgroup by univariate analysis (P < 0.0001). Conclusion: Low intratumoral TS expression was associated with increased overall survival in patients with bile duct cancer who received adjuvant GEM + S-1 chemotherapy. TS is a relevant predictive marker of benefit from adjuvant GEM + S-1 chemotherapy in patients with resected bile duct cancer.