Definitive S-1/mitomycin-C chemoradiotherapy for stage II/III anal canal squamous cell carcinoma: a phase I/II dose-finding and single-arm confirmatory study (JCOG0903).

BACKGROUND: Definitive chemoradiotherapy (CRT) with 5-fluorouracil plus mitomycin-C is a standard treatment for stage II/III squamous cell carcinoma of the anal canal (SCCA). We performed this dose-finding and single-arm confirmatory trial of CRT with S-1 plus mitomycin-C to determine the recommended dose (RD) of S-1 and evaluate its efficacy and safety for locally advanced SCCA. METHODS: Patients with clinical stage II/III SCCA (UICC 6th) received CRT comprising mitomycin-C (10 mg/m2 on days 1 and 29) and S-1 (60 mg/m2/day at level 0 and 80 mg/m2/day at level 1 on days 1-14 and 29-42) with concurrent radiotherapy (59.4 Gy). Dose-finding used a 3 + 3 cohort design. The primary endpoint of the confirmatory trial was 3-year event-free survival. The sample size was 65, with one-sided alpha of 5%, power of 80%, and expected and threshold values of 75% and 60%, respectively. RESULTS: Sixty-nine patients (dose-finding, n = 10; confirmatory, n = 59) were enrolled. The RD of S-1 was determined as 80 mg/m2/day. Three-year event-free survival in 63 eligible patients who received the RD was 65.0% (90% confidence interval 54.1-73.9). Three-year overall, progression-free, and colostomy-free survival rates were 87.3%, 85.7%, and 76.2%, respectively; the complete response rate was 81% on central review. Common grade 3/4 acute toxicities were leukopenia (63.1%), neutropenia (40.0%), diarrhea (20.0%), radiation dermatitis (15.4%), and febrile neutropenia (3.1%). No treatment-related deaths occurred. CONCLUSIONS: Although the primary endpoint was not met, S-1/mitomycin-C chemoradiotherapy had an acceptable toxicity profile and favorable 3-year survival and could be a treatment option for locally advanced SCCA. CLINICAL TRIAL INFORMATION: jRCTs031180002.