Benefit-risk balance of S-1 versus UFT as adjuvant chemotherapy for stage II/III rectal cancer (JFMC35-C1: ACTS-RC)

Jean-Christophe Chiem , Hatem Alharazin , Everardo D Saad , Koji Oba , Masaru Muto , Hisakazu Yamagishi , Junichi Sakamoto , Takaki Yoshikawa , Marc Buyse Author Notes

Content published in The Oncologist, Volume 31, Issue 4, April 2026, oyag081, https://doi.org/10.1093/oncolo/oyag081.

Abstract

Background

Given the superior relapse-free survival (RFS) and different safety profiles of 1 year of adjuvant S-1 or uracil/tegafur (UFT) for stage II/III rectal cancer, the benefit-risk of these 2 regimens was formally assessed using the net treatment benefit (NTB).

Patients and methods

Individual patient data from the Japanese Foundation for Multidisciplinary Treatment of Cancer (JFMC) 35-C1 trial were used. S-1 and UFT were compared regarding RFS, incidence of grade ≥3 symptoms, and incidence of grade ≥3 laboratory abnormalities reported as adverse events (AEs). Laboratory abnormalities and symptoms were analyzed as binary variables and as counts. Univariate and multivariate NTBs were computed for various ways of prioritizing the outcomes.

Results

The univariate NTB for RFS was 9.2% (95% CI, 3.4%-15.2%, P = .005) in favor of S-1. The univariate NTB was not statistically significant for any symptom. For grade ≥3 laboratory AEs, only thrombocytopenia was statistically significant in favor of UFT (NTB = −0.8%; 95% CI, −1.6% to −0.02%; P = .044). In the multivariate analysis considering RFS as the outcome of first priority, the incidence of grade ≥3 symptoms as second, and the incidence of grade ≥3 laboratory abnormalities as third, the multivariate NTB was 8.8% (95% CI, 2.7%-14.9%, P = .014) in favor of S-1. In sensitivity analyses according to age group, the NTB was generally positive for patients <70 years but nonsignificant for those ≥70 years old.

Conclusion

The reanalysis of the JFMC 35-C1 trial suggests that S-1 has a superior benefit-risk to UFT when RFS is considered as the outcome of first priority, followed by the incidence of grade ≥3 symptoms and of grade ≥3 laboratory abnormalities.

Highlights

• S-1 improves RFS vs UFT in patients with rectal cancer, but this alone does not reflect the benefit-risk balance.
• A novel statistical methodology can provide a patient-centric benefit-risk assessment called the net treatment benefit (NTB).
• The NTB prioritizing RFS > Symptoms > Lab abnormalities, shows a significant superiority of S-1.
• The NTB shows age-based difference for S-1: superiority in patients <70 but no significant difference in those ≥70.

Implications for practice

In Japan, both S-1 and UFT are chemotherapy options in the adjuvant treatment of rectal cancer. The benefit-risk balance between these 2 competing treatments can be assessed formally using generalized pairwise comparisons. When this method is used, the superiority of one of the interventions depends on how individual stakeholders prioritize efficacy and safety outcomes based on their personal preferences. Our results suggest that choosing between these 2 agents will depend on the selection and relative prioritization of outcomes that matters to patients with rectal cancer who are candidates to adjuvant chemotherapy.

Continue reading in The Oncologist, Volume 31, Issue 4, April 2026, oyag081, https://doi.org/10.1093/oncolo/oyag081.