Multi-Institutional Phase II Study of S-1 Monotherapy in Advanced Gastric Cancer with Pharmacokinetic and Pharmacogenomic Evaluations

Abstract

This study describes the first phase II study of S-1, a novel oral fluoropyrimidine, in a non-Japanese Asian population with advanced gastric cancer. S-1 was administered twice daily for 28 days every 6 weeks. A pharmacokinetic study was performed on day 28 of cycles 1 and 3. Genomic DNA from peripheral mononuclear cells was analyzed using a cDNA microarraybased comparative genomic hybridization (CGH) method. Thirty-one patients were initially given a dose of 35 mg/m 2 twice daily (bid) (group 1); then, the protocol was amended by increasing the dose to 40 mg/m 2 bid for an additional 31 patients (group 2) because of good tolerability to S-1. The overall response rate was 19.3% (95% confidence interval, 9.2%-29.5%). Over a median follow-up duration of 265 days, the median time to progression and overall survival time were 126 and 264 days, respectively. The 1-year survival rate was 34%. There was no grade 4 toxicity and the major adverse event was anemia. Pharmacokinetic parameters were similar to those of the previous Japanese reports. Microarray CGH identified 18 genes with copy number changes that were associated with hemoglobin reduction with S-1 treatment. A logistic regression analysis, integrating one clinical parameter (initial hemoglobin level) combined with three genetic copy number variations (HIST1H2BL, C10orf127, and XPNPEP2), provided a predictive model for the development of severe hemoglobin reduction. In conclusion, this study showed the feasibility of using S-1 at 35 mg/m 2 bid in gastric cancer. We suggest that the pharmacogenomic markers identified in this study may be potential candidates for predicting anemia after S-1 treatment. The Oncologist 2007;12:543-554

A multi-center phase II study of S-1 plus paclitaxel as first-line therapy for patients with advanced or recurrent unresectable gastric cancer

“…S-1, as a prodrug of 5-FU, has been developed to increase the eYcacy and decrease the gastrointestinal toxicities of 5-FU [4,8]. In several phase II studies, S-1 alone has had modest antitumor activity in advanced gastric cancer [3,11,14,21,22]. A phase III trial of comparing S-1 with 5-FU was reported that of S-1 showed not inferior to 5-FU in overall survival (S-1 vs. 5-FU; 11.4 month vs. 10.8 month) [19].…”

“…In the Korean study, the common toxicities were anemia and abdominal pain, and the incidence of toxicities tended to increase at a dose of 80 mg/m 2 [3,11]. In the European study, the common toxicities were diarrhea and hand-foot syndrome rather than hematological toxicity and the toxicities were decreased at the 70 mg/m 2 dose [3].…”

“…The response rates with S-1 monotherapy, in patients with advanced gastric cancer, as the Wrst-line therapy were variable, 44-49% in Japan, 16.1% in Korea and 26.1% in Europe [3,11,14,21,22]. The response rates reported from the Japanese trials were higher than those from the Korean and European trials were.…”

“…In a Korean and European phase II trial of S-1 monotherapy, 70 and 80 mg/m 2 doses of S-1 were evaluated [3,11]. In the Korean study, the common toxicities were anemia and abdominal pain, and the incidence of toxicities tended to increase at a dose of 80 mg/m 2 [3,11].…”

“…In Wve clinical trials, including three Japanese trials, the response rate after treatment with S-1 was 20-50% in patients with advanced gastric cancer as a single agent, when it was administered for 4 weeks with 2 weeks oV [3,11,14,21,22]. The main side eVects of S-1 treatment were diarrhea, fatigue, anemia, and neutropenia.…”