Key Takeaways & Executive Findings
- •• • S-1 adjuvant chemotherapy significantly improved 3-year disease-free survival (DFS) by 10.6 percentage points (72.3% vs. 61.7%; HR 0.68; 95% CI 0.55-0.84; p < 0.001) compared to observation, representing a 32% relative reduction in risk of recurrence or death. • • Overall survival (OS) at 3 years was also significantly higher in the S-1 group (82.4% vs. 74.6%; HR 0.72; 95% CI 0.56-0.93; p = 0.012), translating to a 28% relative reduction in mortality risk. • • The safety profile was manageable: grade 3/4 adverse events occurred in 28.4% of patients, with neutropenia (12.3%), anorexia (8.7%), and diarrhea (5.2%) being the most frequent; no treatment-related deaths were reported. • • High treatment adherence (78.6% completed the full 1-year course) indicates that S-1 is a feasible oral adjuvant regimen, potentially improving patient compliance compared to intravenous chemotherapy, which is critical for real-world effectiveness.
Abstract
This multicenter, randomized, controlled trial evaluated the efficacy and safety of adjuvant chemotherapy with S-1 in patients with stage II/III gastric cancer following curative resection. A total of 1,025 patients were randomized to receive either S-1 (80 mg/m²/day on days 1-28 every 5 weeks for 1 year) or observation. The primary endpoint was 3-year disease-free survival (DFS). Secondary endpoints included overall survival (OS), safety, and quality of life. At a median follow-up of 38.5 months, the 3-year DFS rate was significantly higher in the S-1 group (72.3%) compared to the observation group (61.7%) (hazard ratio [HR] 0.68; 95% confidence interval [CI] 0.55-0.84; p < 0.001). The 3-year OS rate was also improved (82.4% vs. 74.6%; HR 0.72; 95% CI 0.56-0.93; p = 0.012). Grade 3/4 adverse events occurred in 28.4% of S-1 patients, with neutropenia (12.3%), anorexia (8.7%), and diarrhea (5.2%) being most common. Treatment adherence was high, with 78.6% of patients completing the full 1-year course. Subgroup analyses demonstrated consistent benefit across tumor stages and histological types. These findings support S-1 as a standard adjuvant therapy for stage II/III gastric cancer in Asian populations, offering a well-tolerated oral alternative to intravenous regimens.
1. Introduction
Gastric cancer remains a leading cause of cancer-related mortality worldwide, particularly in East Asia. Despite curative resection, the 5-year survival rate for stage II/III disease is only 30-50% due to high rates of recurrence. Adjuvant chemotherapy has been shown to improve survival, but the optimal regimen remains debated. Intravenous regimens such as capecitabine plus oxaliplatin (XELOX) or docetaxel plus S-1 (DS) have demonstrated efficacy but are associated with significant toxicity and logistical burdens, including the need for central venous access and frequent hospital visits. This has limited their widespread adoption, especially in older or frail patients. There is a clear clinical need for an effective, well-tolerated, and orally administered adjuvant therapy that can be easily integrated into routine practice.
The present multicenter, randomized, controlled trial was designed to address this bottleneck by evaluating the efficacy and safety of S-1 monotherapy, an oral fluoropyrimidine, as adjuvant treatment for stage II/III gastric cancer. S-1 combines tegafur, gimeracil, and oteracil, and has shown promising activity in advanced gastric cancer. By comparing S-1 to observation alone, this study provides high-level evidence on whether oral adjuvant therapy can improve survival outcomes without compromising quality of life. The results demonstrate a significant improvement in both disease-free and overall survival, with a manageable toxicity profile, supporting S-1 as a standard of care in this patient population.
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ZHANG Wei, LI Ming, WANG Fang, et al. (2025). Efficacy and Safety of Adjuvant Chemotherapy with S-1 in Patients with Stage II/III Gastric Cancer: A Multicenter, Randomized, Controlled Trial. Chinese Journal of New Drugs. https://doi.org/pub_80__articleID_213
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Frequently Asked Questions
What was the rationale for choosing S-1 monotherapy instead of combination regimens like XELOX or DS, and how does its efficacy compare in terms of hazard ratios?
S-1 monotherapy was selected to provide a less toxic, orally administered alternative to intravenous combinations, which are often associated with higher rates of neuropathy and neutropenia. In our trial, S-1 achieved a 3-year DFS HR of 0.68 (95% CI 0.55-0.84) compared to observation. While cross-trial comparisons are limited, this effect size is comparable to that reported for XELOX (HR ~0.66) and DS (HR ~0.63) in similar patient populations, suggesting that S-1 monotherapy offers a favorable risk-benefit profile, particularly for patients who cannot tolerate intensive regimens.
What were the most common grade 3/4 adverse events, and how did they impact treatment adherence?
The most common grade 3/4 adverse events were neutropenia (12.3%), anorexia (8.7%), and diarrhea (5.2%). Despite these, treatment adherence was high, with 78.6% of patients completing the full 1-year course. This suggests that the toxicity was manageable with appropriate supportive care and dose modifications, and that S-1 is a feasible long-term oral therapy.
Were there any subgroup differences in treatment benefit, particularly by tumor stage or histological type?
Subgroup analyses showed consistent benefit of S-1 across all prespecified subgroups, including tumor stage (II vs. III) and histological type (intestinal vs. diffuse). The hazard ratio for DFS was 0.65 (95% CI 0.48-0.88) in stage II and 0.70 (95% CI 0.54-0.91) in stage III, indicating that the benefit was not limited to a particular subgroup.
How does the safety profile of S-1 compare to intravenous fluoropyrimidine-based regimens, and what are the implications for clinical practice?
S-1 is associated with lower rates of hand-foot syndrome and neutropenia compared to capecitabine-based regimens, and it avoids the need for central venous access and infusion pumps. In our trial, the incidence of grade 3/4 neutropenia was 12.3%, which is lower than that reported for XELOX (approximately 20%). This oral regimen may improve patient convenience and reduce healthcare resource utilization, making it an attractive option for adjuvant therapy.
What was the median follow-up duration, and were there any late toxicities or secondary malignancies observed?
The median follow-up was 38.5 months. No significant late toxicities or secondary malignancies were reported during the follow-up period. The safety profile remained consistent with the known long-term tolerability of S-1, and no new safety signals were identified.
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