Phase III Trial Indicates That S-1 Monotherapy Should Remain Standard Treatment of Locally Advanced Gastric Cancer in Japan


Key Points

  • Sequential paclitaxel plus uracil or S-1 did not improve disease-free survival over uracil or S-1 monotherapy.
  • S-1 was associated with significantly better disease-free survival and overall survival vs uracil.

The oral fluoropyrimidine S-1 is standard treatment for locally advanced gastric cancer in Japan. In a Japanese phase III trial (SAMIT) in locally advanced disease reported in The Lancet Oncology, Tsuburaya et al found that sequential paclitaxel plus tegafur and uracil or S-1 did not improve disease-free survival over monotherapy with uracil or S-1 alone and that S-1 was associated with improved disease-free survival and overall survival compared with uracil.

Study Details

In this 2×2 factorial trial, 1,433 patients from 230 Japanese hospitals aged 20 to 80 years with T4a or T4b gastric cancer, D2 dissection, and Eastern Cooperative Oncology group performance status of  0 or 1 were randomly assigned between August 2004 and September 2009 to receive uracil at 267 mg/m² per day (n = 359) or S-1 at 80 mg/m² per day (n = 364) for 14 days with a 7-day rest period or three courses of intermittent weekly paclitaxel 80 mg/m² followed by either uracil (n = 355) or S-1 (n = 355). Treatment lasted 48 weeks in monotherapy groups and 49 weeks in sequential treatment groups.

The primary endpoint was disease-free survival in the intention to treat population. The comparison of monotherapy was a noninferiority analysis of disease-free survival with uracil vs S-1 with a noninferiority margin of 1.33.

Survival Outcomes

Median follow-up ranged from 61.3 to 65.5 months in the four groups. Three-year disease-free survival rates were 54.0% with monotherapy vs 57.2% with sequential therapy (hazard ratio [HR] = 0.92, P = .273) and 53.0% with uracil alone vs 58.2% with S-1 alone (HR = 0.81, P = .0048; P = .151 for noninferiority).

Three-year overall survival was 55.8% with monotherapy vs 59.3% with sequential therapy (HR = 0.93, P = .342) and 54.3% with uracil vs 60.7% with S-1 (HR = 0.81, P = .013).


The most common grade 3 or 4 hematologic adverse event was neutropenia, occurring in 11% of the uracil group, 13% of the S-1 group, 13% of the paclitaxel/uracil group, and 23% of the paclitaxel/S-1 group. The most common grade 3 or 4 nonhematologic adverse event was anorexia, occurring in 6%, 7%, 2%, and 5%, respectively.

The investigators concluded, “Sequential treatment did not improve disease-free survival, and [uracil] was not non-inferior to S-1 (and S-1 was superior to [uracil]), therefore S-1 monotherapy should remain the standard treatment for locally advanced gastric cancer in Japan.”

Kazuhiro Yoshida, MD, of Gifu University, Graduate School of Medicine, is the corresponding author for the Lancet Oncology article.

The study was funded by the Japanese Epidemiological and Clinical Research Information Network. For full disclosures of the study authors, visit

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