K. Akahoshi1, D. Ban1, R. Kuboki1, S. Matsumura1, Y. Mitsunori1, T. Ochiai1, A. Kudo1, M. Tanabe1 1Tokyo Medical And Dental University,Hepato-Biliary-Pancreatic Surgery,Bunkyo-ku, Tokyo, Japan
Introduction: To improve the prognosis of cholangiocarcinoma, we investigated biomarkers that can contribute to select the patients who can take benefit from adjuvant chemotherapy after surgical resection.
Methods: Of 170 consecutive patients who underwent surgical resection for cholangiocarcinoma between 2004 and 2015, 26 patients who received gemcitabine adjuvant chemotherapy (the GEM group), 36 patients who received S-1 adjuvant chemotherapy (the S-1 group) and 103 patients who didn’t receive adjuvant chemotherapy (the NC group) were enrolled in this study. Propensity score matching was performed to adjust for differences in patient characteristics, then 36 patients were selected from the NC group. Immunohistochemical analysis of orotate phosphoribosyltransferase (OPRT) and human equilibrative nucleoside transporter 1 (hENT1) was performed, and the correlation between the expression and cancer recurrence was analyzed.
Results: Before the propensity matching selection, the NC group was associated with higher prevalence of distal cholangiocarcinoma (p=0.03) and higher ASA score (p=0.03) than the GEM and the S-1 groups. After the matching, there were no differences among the GEM(n=26), S-1(n=36) and the NC(n=36) groups. Immunohistochemistry of resected tumor tissues was performed. Of the 98 patients, 46 and 52 showed high OPRT and hENT1 expression, respectively. Distal cholangiocarcinoma was more likely to exhibit high OPRT and hENT1 expression (p<0.01). Among high OPRT patients, the disease free survival(DFS) rates of the GEM, S-1, and NC groups at 5 years were 28.8%, 50.8% and 22.9%, respectively. The DFS of the S-1 group was significantly better than the NC group (p=0.037) and the DFS of the GEM group was similar to the NC group (p=0.85). On the other hand, among low OPRT patients, the DFS rates of the GEM, S-1, and NC groups at 5 years were 23.1%, 18.0% and 27.6%, respectively. There were no significant differences of the DFS among them. The same analysis was performed about hENT1. No significant improve of the DFS was observed by adjuvant chemotherapy in both high and low hENT1 expression patients. Multivariate analysis of all patients (n=98) determined that residual tumor (HR=2.533; 95% CI:1.548-4.144; p=0.001) and lymph node metastases (HR=1.708; 95% CI:1.031-2.830; p=0.038) were independent prognostic factors for cancer recurrence, whereas S-1 adjuvant chemotherapy wasn’t a prognostic factor. However, multivariate analysis of the high OPRT patients (n=46) determined that S-1 adjuvant chemotherapy (HR=0.309; 95% CI:0.120-0.796; p=0.015) and lymph node metastases (HR=2.594; 95% CI:1.099-6.121; p=0.030) were prognostic factors for recurrence.
Conclusion:
S-1 adjuvant chemotherapy for cholangiocarcinoma patients was effective to improve DFS only in the patients who exhibited high tumoral OPRT expression. OPRT is expected to contribute to the optimization and personalization of adjuvant chemotherapy for cholangiocarcinoma.