PURPOSE S-1 is a standard postoperative adjuvant chemotherapy for patients with stage II or III gastric cancer in Asia. Neoadjuvant or perioperative strategies dominate in Western countries, and docetaxel has recently shown significant survival benefits when combined with other standard regimens in advanced cancer and perioperative settings. PATIENTS AND METHODS This randomized phase III study was designed to prove the superiority of postoperative S-1 plus docetaxel over S-1 alone for R0 resection of pathologic stage III gastric cancer. The sample size of 1,100 patients was necessary to detect a 7% increase in 3-year relapse-free survival as the primary end point (hazard ratio, 0.78; 2-sided α = .05; β = .2). RESULTS The second interim analysis was conducted when the number of events reached 216 among 915 enrolled patients (median follow-up, 12.5 months). Analysis demonstrated the superiority of S-1 plus docetaxel (66%) to S-1 (50%) for 3-year relapse-free survival (hazard ratio, 0.632; 99.99% CI, 0.400 to 0.998; stratified log-rank test, P < .001), and enrollment was terminated as recommended by the independent data and safety monitoring committee. Incidences of grade 3 or greater adverse events, particularly neutropenia and leukopenia, were higher in the S-1 plus docetaxel group, but all events were manageable. CONCLUSION Addition of docetaxel to S-1 is effective with few safety concerns in patients with stage III gastric cancer. The present findings may also be applicable in countries in which perioperative adjuvant chemotherapy or chemoradiation is not standard.

Purpose: EGF receptor (EGFR) and HER2 positivity are considered to be negative prognostic factors in gastric cancer. Biomarker analysis was conducted to evaluate the impact of EGFR and HER2 expression on the outcome of patients enrolled in the Adjuvant Chemotherapy Trial of TS-1 for Gastric Cancer (ACTS-GC), a randomized controlled trial comparing postoperative adjuvant S-1 therapy with surgery alone in 1,059 patients with stage II/III gastric cancer.Experimental Design: Formalin-fixed, paraffin-embedded surgical specimens were retrospectively examined in 829 patients (78.3%). The effects of EGFR and HER2 positivity on survival were analyzed on the basis of the 5-year survival data from the study. EGFR positivity was defined as an immunohistochemistry (IHC) score of 3þ, and HER2 positivity as an IHC score of 3þ or an IHC score of 2þ with a positive dual-color in situ hybridization status.Results: EGFR and HER2 were positive in 75 (9.0%) and 113 (13.6%) patients, respectively. The overall and relapse-free survival rates were significantly lower in EGFR-positive patients than in EGFR-negative patients, whereas they were similar in HER2-positive and HER2-negative patients. Multivariate analysis showed that EGFR positivity correlated with poor outcomes [HR ¼ 1.504; 95% confidence interval (CI) ¼ 1.020-2.149; P ¼ 0.040]. Treatment with S-1 improved survival compared with surgery alone, irrespective of EGFR and HER2 status.Conclusions: EGFR positivity, but not HER2 positivity, was associated with poor patient outcomes after curative resection of stage II/III gastric cancer. There was no interaction between S-1 and EGFR or HER2 status with respect to survival outcome. Clin Cancer Res; 18(21); 5992-6000. Ó2012 AACR.

Activation of 5-fluorouracil into its nucleotides requires phosphorylation by three pathways involving orotate phosphoribosyltransferase (OPRT), uridine phosphorylase (UP), or thymidine phosphorylase (TP). In this study, we investigated the association between gene expressions of these three enzymes and antitumour effect. Gene expressions in primary colorectal tumours were analysed by a real-time reverse transcriptional -polymerase chain reaction method in 37 patients receiving oral treatment of tegafururacil and leucovorin for metastatic diseases. The median values of OPRT mRNA expressions were 1.39 and 0.85 for responding tumours and nonresponding tumours, respectively, showing a statistically significant difference (P ¼ 0.0008). Responding tumours had statistically lower expressions of TP mRNA than nonresponding tumours (P ¼ 0.006). However, there was no difference in UP mRNA expression between responding and nonresponding tumours. Patients with high OPRT (X1.0) gene expression survived longer than those with low OPRT (o1.0) expression. Dihydropyrimidine dehydrogenase (DPD) gene expressions were measured. Responding tumours had a statistically higher OPRT/DPD ratio than the nonresponding ones (P ¼ 0.003). When the median value of the OPRT/DPD ratio was selected as the cutoff value, patients with a high OPRT/DPD ratio survived statistically longer than those with a low ratio (P ¼ 0.0014). In conclusion, both the expression of OPRT gene and the OPRT/DPD ratio might be useful as predictive parameters for the efficacy of fluoropyrimidine-based chemotherapy for metastatic colorectal cancer. An important anticancer agent widely used in the treatment of colorectal cancers, 5-fluorouracil (5-FU), is catabolised rapidly to the inactive metabolite dihydrofluorouracil (FUH 2 ) by the first and rate-limiting enzyme-dihydropyrimidine dehydrogenase (DPD) (Heggie et al, 1987). The main mode of action of 5-FU is thought to be through its active metabolite: 5-fluoro-uridine-5 0 -triphosphate (FUTP) or 5-fluoro-2 0 -deoxyuridine-5 0 -monophosphate (FdUMP) (Danenberg, 1977). Metabolites such as FUTP can be incorporated into RNA, while FdUMP suppresses thymidylate synthase (TS), an essential DNA de novo synthetic enzyme that catalyses the methylation of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) (Danenberg, 1977;Pinedo and Peters, 1988).With combined DPD and TS gene expressions, both response and survival could be predicted more precisely than on the bases of only one gene expression. No tumour with both high DPD and high TS expression responded to tegafur-uracil (UFT), an oral fluoropyrimidine, and leucovorin (LV) therapy, but not even all tumours with both low DPD and low TS expression responded to the therapy, such cases having a response rate of 75% (Ichikawa et al, 2003). Salonga et al (2000) reported that only one of 12 tumours with both low DPD and low TS expression was a nonresponder to 5-FU, but that case had a high thymidine phosphorylase (TP) expression. These data suggested that combined...

The predictive values of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) gene expressions were retrospectively evaluated in patients with gastric cancer treated by a regimen containing S-1. The study population consisted of 53 patients registered into different two phase II studies for metastatic gastric cancer; 27 patients treated by S-1-alone study: 26 patients treated with S-1 combined with irinotecan (CPT-11). TS and DPD gene expressions in primary tumours were measured by the realtime reverse transcription PCR method. There was no statistical difference in DPD gene expression in terms of response in cases treated with S-1 alone and those treated with S-1 plus CPT-11. TS mRNA of responding tumours was lower than that of nonresponding ones when treated with S-1 (Po0.005). In the S-1-alone group, taking TS cutoff as the median values, the response rate in the low TS group was 50%, but only 8% in the high TS group (Po0.05). Patients with low TS gene expression survived longer than those with high TS gene expression (Po0.0001). However, there was no statistically significant difference in response rate and survival between patients with low TS tumours and those with high TS tumours, when the cutoff was taken as the median value of TS gene expression in the group treated with S-1 plus CPT-11. In conclusion, treatment effects of S-1 monotherapy for gastric cancer were determined by the status of TS gene expression, regardless of DPD gene expression. TS predictive power was overcome by CPT-11 combination therapy with S-1. The main mode of action of 5-fluorouracil (5-FU) is thought to be through its active metabolite, 5-fluoro-deoxyuridine-monophosphate (FdUMP), which suppresses thymidylate synthase (TS), an essential DNA synthetic enzyme that catalyses the methylation of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) (Langenbach et al, 1972;Peters et al, 1995). 5-FU is catabolised to 2-fluoro-b-alanine by dihydropyrimidine dehydrogenase (DPD), the first and rate-limiting enzyme (Heggie et al, 1987).S-1 is a new oral fluorinated pyrimidine, in which tegafur (FT) has been combined with two 5-FU modulating substances: 5-chloro-2,4-dihydroxypyrimidine (gimeracil, CDHP), and potassium oxonate (oteracil potassium, Oxo), in a molar ratio of FT: CDHP: Oxo ¼ 1 : 0.4 : 1 (Shirasaka et al, 1996). FT is a prodrug of 5-fluorouracil (FU), which is absorbed after oral ingestion followed by conversion to 5-FU. CDHP reversibly inhibits the activity of DPD , resulting in the increase of antitumour activity (Tatsumi et al, 1987). Two phase II studies of S-1 showed activity in gastric cancer, accompanied by mild-to-moderate toxicity. The response rate was 44 -49% and the median survival time was 207 -250 days, with 1-and 2-year survival rates of 36 -37 and 14%, respectively (Sakata et al, 1998;Koizumi et al, 2000).Irinotecan hydrochloride (CPT-11) is a water-soluble, semisynthetic derivative of camptothecin (CPT) that retains the original antitumour effects of CPT-11 due to the inhibition ...

We evaluated the expression of 5-FU pathway genes in prechemotherapeutic fresh frozen samples obtained from primary tumors to predict response and survival of 59 metastatic gastric cancer patients treated with S-1 monotherapy as first line treatment. Five 5-FU pathway genes, including thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT), thymidine phosphorylase (TP) and uridine phosphorylase (UP), were analyzed by the quantitative real-time reverse transcriptional PCR method. Median values of each gene were selected for cut-off values separating high and low gene expressions. In univariate analyses, low TS, high OPRT and low TP were significantly associated with a tumor shrinkage and a long survival, whereas DPD and UP gene expressions did not correlate with response and survival. Multivariate analyses revealed that independent variables were OPRT and TS for response and TS and TP for survival. When OPRT and TS were combined, a significantly increased accuracy rate of 91.5% was seen for response. Similarly, an increased hazard ratio of 10.29 was observed for survival in patients possessing low TS and low TP, compared with those with high TS or high TP. The simple combinations of 2 genes, OPRT and TS for response and TS and TP for survival, may allow identification of gastric cancer patients who will benefit from S-1 chemotherapy. ' 2006 Wiley-Liss, Inc.Key words: orotate phosphoribosyltransferase; thymidylate synthase; thymidine phosphorylase; dihydropyrimidine dehydrogenase; S-1 The significant survival benefit of 5-fluorouracil (5-FU)-based chemotherapy for metastatic gastric cancer compared with best supportive care is reported.1,2 5-FU combined with cisplatin has been referred to as standard chemotherapy for metastatic gastric cancer, with the median survival time ranging from 7.3 to 10.5 months.1 During the last few years, additional drugs, including oxaliplatin, taxanes, irinotecan, and oral fluoropyrimidines such as S-1, have been introduced into chemotherapy regimens for the improvement of survival. 2,3 This approach has resulted in the increase of response rate, but has not changed the median survival time under 12 months, often with a higher frequency of severe adverse events, even acceptable.1,2 Thus, there is a need for diagnostic methods that allow prediction of clinical outcome and enable a pretherapeutic discrimination of treatment effect.The antitumor effect of 5-FU is the inhibitor of thymidylate synthase (TS), an essential DNA synthetic enzyme, by 5-fluoro-2 0 -deoxyuridine-5 0 -monophosphate (FdUMP), as well as incorporation of 5-FU metabolites into RNA and DNA. 4 The initial metabolism of 5-FU into nucleotides is essential for its action by one or more of the following 3 pathways: (i) directly to 5-fluorouridine 5 0 -monophosphate (FUMP) by orotate phosphoribosyltransferase (OPRT); (ii) indirectly to FUMP in a sequence of reactions with conversion of 5-FU to 5-fluorouridine phosphorylated by uridine phosphorylase (UP); (iii) indirectly to ...