Updated 5-year survival and exploratory T x N subset analyses of ACTS-CC trial: a randomised controlled trial of S-1 versus tegafur-uracil/leucovorin as adjuvant chemotherapy for stage III colon cancer

Abstract

Objective: Adjuvant Chemotherapy Trial of TS-1 for Colon Cancer (ACTS-CC), a randomised phase III trial, demonstrated that adjuvant therapy with S-1 for stage III colon cancer was non-inferior in 3-year disease-free survival (DFS) to that of tegafur-uracil plus leucovorin (UFT/LV). We updated DFS and overall survival (OS) and performed T x N subset analysis.

Methods: A total of 1518 patients with curatively resected stage III colon cancer were randomly assigned to receive S-1 (80-120 mg/day on days 1-28 every 42 days, four courses) or UFT/LV (UFT: 300-600 mg/day and LV: 75 mg/day on days 1-28 every 35 days, five courses).

Results: The 5-year DFS rates of the S-1 and UFT/LV group were 70.2 % and 66.9 %, respectively (HR 0.88; 95% CI 0.74 to 1.06; p=0.177), and non-inferiority of DFS was reconfirmed with a median of 63.5-month follow-up. The similarity of OS was also confirmed (HR 0.92; 95% CI 0.72 to 1.17; p=0.488); 5-year OS rates of the S-1 and UFT/LV group were 86.0 % and 84.4 %, respectively. No significant interactions were identified between the major baseline characteristics and DFS of the S-1 and UFT/LV groups, except for histological type; S-1 was more favourable in patients with poorly differentiated adenocarcinoma. Patient outcomes were well separated by TNM-substages (IIIA/IIIB/IIIC). With the patients divided into 20 subsets by T and N factors, the DFS and OS rates of T3 and N1 subset, which accounted for 62 % of stage IIIB patients and 44 % of all studied subjects, were significantly better than those of the other subsets in stage IIIB and similar to those of stage IIIA.

Conclusions: Adjuvant therapy of S-1 for stage III colon cancer was reconfirmed to be non-inferior in DFS to those of UFT/LV after long follow-up. No difference in OS was also demonstrated. T3N1 patients might be considered separately from other patients included in stage IIIB because of its favourable outcome.

Trial registration number: NCT00660894.

Keywords: S-1; TNM classification; adjuvant chemotherapy; colon cancer; tegafur-uracil (UFT).

Conflict of interest statement

Competing interests: MI has received honoraria from Taiho Pharmaceutical Co. Ltd., and Merck Serono Co. Ltd.; research funding from Taiho and Yakult Honsha Co. Ltd. KS received honoraria and research funding from Taiho Pharmaceutical Co. Ltd. and Chugai Pharmaceutical Co. Ltd. All remaining authors have declared no conflicts of interest.

Figures

Figure 1

CONSORT diagram. CONSORT, Consolidated Standards of Reporting Trials; LV, leucovorin; S-1, tegafur-gimeracil-oteracil potassium; UFT, tegafur-uracil.

Figure 2

Survival curves. (A) Disease-free survival (DFS). (B) Overall survival (OS). LV, leucovorin; No., number; S-1, tegafur-gimeracil-oteracil potassium; UFT, tegafur-uracil.

Figure 3

Subgroup analysis of disease-free survival in the S-1 group compared with the UFT/LV group. Annotation: right-sided colon includes caecum, ascending and transverse colon. Left-sided colon includes descending and sigmoid colon. BMI, body mass index; CEA, carcinoembryonic antigen; DFS, disease-free survival; LN, lymph node; LV, leucovorin; muc, mucinous adenocarcinoma; pap, papillary adenocarcinoma; por, poorly differentiated adenocarcinoma; sig, signet-ring cell carcinoma; S-1, tegafur-gimeracil-oteracil potassium; tub, tubular adenocarcinoma; UFT, tegafur-uracil.

Figure 4

Five-year DFS and OS rates of T x N subsets. *: DFS rate at 5 years could not be estimated (not reached). DFS, disease-free survival; OS, overall survival.

Figure 5

Survival curves of the modified four TNM substages. (A) Disease-free survival (DFS). (B) Overall survival (OS). Annotation: IIIB-1: T3N1, IIIB-2: stage IIIB other than T3N1.

Figure 6

Three-year DFS rates of T x N subsets of the ACTS-CC trial and IDEA study. Annotation: definitions of DFS in ACTS-CC and IDEA were different. In the ACTS-CC trial, DFS was defined as the time from randomisation to recurrence, second cancers or death, whichever occurred first. ‘Second cancers’ included metachronous cancers developed in both colorectum and the other organs. In the IDEA study, DFS was defined as the time from randomisation to the date of a first relapse, the diagnosis of a secondary colorectal cancer after the initial diagnosis or death from any cause, whichever occurred first. Malignancies developed in the other organs, that is, breast, head and neck, were not included. ACTS-CC, Adjuvant Chemotherapy Trial of TS-1 for Colon Cancer; DFS, disease-free survival; IDEA, International Duration Evaluation of Adjuvant Chemotherapy.