Randomized phase III trial of adjuvant chemotherapy with S-1 after curative treatment in patients with squamous-cell carcinoma of the head and neck (ACTS-HNC)

Kiyoaki Tsukahara, Akira Kubota, Yasuhisa Hasegawa, Hideki Takemura, Tomonori Terada, Takahide Taguchi, Kunihiko Nagahara, Hiroaki Nakatani, Kunitoshi Yoshino, Yuichiro Higaki, Shigemichi Iwae, Takeshi Beppu, Yutaka Hanamure, Kichinobu Tomita, Naoyuki Kohno, Kazuyoshi Kawabata, Masanori Fukushima, Satoshi Teramukai, Masato Fujii, ACTS-HNC group, M Fujii, A Kubota, K Kawabata, N Kohno, K Tomita, K Yoshino, M Fukushima, A Kida, S Kamata, T Yoshihara, M Sugita, M Asai, S Teramukai, Kiyoaki Tsukahara, Akira Kubota, Yasuhisa Hasegawa, Hideki Takemura, Tomonori Terada, Takahide Taguchi, Kunihiko Nagahara, Hiroaki Nakatani, Kunitoshi Yoshino, Yuichiro Higaki, Shigemichi Iwae, Takeshi Beppu, Yutaka Hanamure, Kichinobu Tomita, Naoyuki Kohno, Kazuyoshi Kawabata, Masanori Fukushima, Satoshi Teramukai, Masato Fujii, ACTS-HNC group, M Fujii, A Kubota, K Kawabata, N Kohno, K Tomita, K Yoshino, M Fukushima, A Kida, S Kamata, T Yoshihara, M Sugita, M Asai, S Teramukai

Abstract

Background: We conducted a phase III study to evaluate S-1 as compared with UFT as control in patients after curative therapy for stage III, IVA, or IVB squamous-cell carcinoma of the head and neck (SCCHN).

Patients and methods: Patients were randomly assigned to the UFT group (300 or 400 mg day-1 for 1 year) or the S-1 group (80, 100, or 120 mg day-1 for 1 year). The primary end point was disease-free survival (DFS). Secondary end points were relapse-free survival, overall survival (OS), and safety.

Results: A total of 526 patients were enrolled, and 505 were eligible for analysis. The 3-year DFS rate was 60.0% in the UFT group and 64.1% in the S-1 group (HR, 0.87; 95%CI, 0.66-1.16; p = 0.34). The 3-year OS rate was 75.8% and 82.9%, respectively (HR, 0.64; 95% CI, 0.44-0.94; p = 0.022). Among grade 3 or higher adverse events, the incidences of leukopenia (5.2%), neutropenia (3.6%), thrombocytopenia (2.0%), and mucositis/stomatitis (2.4%) were significantly higher in the S-1 group.

Conclusions: Although DFS did not differ significantly between the groups, OS was significantly better in the S-1 group than in the UFT group. S-1 is considered a treatment option after curative therapy for stage III, IVA, IVB SCCHN.

Trial registration: ClinicalTrials.gov NCT00336947 https://ichgcp.net/clinical-trials-registry/NCT00336947.

Conflict of interest statement

Competing Interests: H. Takemura, T. Taguchi, K. Nagahara, K. Tomita, S. Teramukai and M. Fujii received advisory role fee from Taiho Pharmaceutical. K. Tsukahara, A. Kubota, Y. Hasegawa, H. Takemura, T. Taguchi, K. Nagahara, H. Nakatani, K. Yoshino, K. Tomita, N. Kohno, S. Teramukai and M. Fujii received speaker honoraria from Taiho Pharmaceutical. K. Tsukahara, A. Kubota, H. Takemura, T. Taguchi, K. Nagahara, K. Tomita, N. Kohno and M. Fujii received unrestricted research grant from Taiho Pharmaceutical. The remaining authors declare no conflict of interest. This does not alter the authors' adherence to PLOS ONE policies regarding sharing data and materials.

Figures

Fig 1. Definition of definitive treatment.
Fig 1. Definition of definitive treatment.
Abbreviations: RT, radiotherapy. CRT, chemoradiotherapy.
Fig 2. CONSORT diagram.
Fig 2. CONSORT diagram.
ITT, Intention-to-treat.
Fig 3. Kaplan-Meier estimates of disease-free survival…
Fig 3. Kaplan-Meier estimates of disease-free survival (A), relapse-free survival (B), and overall survival (C).
Fig 4. Subgroup Analysis: disease-free survival and…
Fig 4. Subgroup Analysis: disease-free survival and overall survival.
With/without chemotherapy†: Whether chemotherapy was received at curative treatment.
Fig 5. Subgroup analysis: relapse-free survival.
Fig 5. Subgroup analysis: relapse-free survival.
With/without chemotherapy†: Whether chemotherapy was received at curative treatment
Fig 6. Cumulative rates of locoregional recurrence…
Fig 6. Cumulative rates of locoregional recurrence (A) and distant metastasis (B).
(A) One patient with secondary cancer before locoregional recurrence was censored. (B) One patient with secondary cancer before distant metastasis was censored.
Fig 7. Survival from recurrence to death…
Fig 7. Survival from recurrence to death in patients with local recurrence/cervical lymph node recurrence (A) and in patients with distant metastasis (B).

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