Dose-finding and single-arm confirmatory study of definitive chemoradiotherapy (dCRT) with S-1/mitomycin-C (MMC) in patients (pts) with clinical (c) stage II/III squamous cell carcinoma of the anal canal (SCCA): JCOG0903.

Abstract

686 Background: dCRT with 5-FU/MMC is a standard treatment for cStage II/III SCCA. S-1 is an oral fluoropyrimidine and has a greater effect on radiosensitivity. We conducted this trial of dCRT with S-1/MMC to determine the recommended dose (RD) of S-1 in phase I part (P I) and to evaluate the efficacy and safety in phase II part (P II) for cStage II/III SCCA. When the primary endpoint in P II part is proven to be satisfactory, we can regard this combined treatment as the new standard treatment. Methods: Eligibility criteria included histologically proven SCCA, cStage II/III (UICC 6th), PS 0-1, and age 20-80 years. dCRT consisted of MMC (10 mg/m2 on days 1, 29) and S-1 (60 mg/m2/d in level 0 and 80 mg/m2/d in level 1 on days 1-14, 29-42) with concurrent 3-dimensional RT of 59.4 Gy/33fr. The P I adopted the 3+3 cohort design. The primary endpoint of P II was proportion of 3-year event-free survival (% 3-year-EFS). The sample size was 65 in the P II, with one-sided alpha of 5% and power of 80%, threshold and expected % 3-year EFS as 60% and 75%. Results: From Feb/2010 to Mar/2015, 69 pts (3 in level 0 and 66 [7 in P I and 59 in P II] in level 1) were enrolled. Pts’s backgrounds for level 1 were as follows: M/F, 12/54; Age, median 64 (range 33-80); cStage II/IIIA/IIIB, 29/9/28. Three in level 1 were ineligible and 63 eligible assigned to level 1 were included in efficacy analysis. In the P I, considering the details of DLTs, RD of S-1 was determined as 80 mg/m2/d. In the 63 eligible of level 1, %3-year EFS was 65.0% (90% CI 54.1-73.9%). % 3-year OS, PFS, and colostomy-free survival were 87.3% (95% CI 76.2-93.4%), 85.7% (74.3-92.3%), and 76.2% (63.7-84.9%), respectively. The complete response rate was 81% on central review. Among 65 pts receiving level 1 dCRT, common grade 3 or 4 acute toxicities were leukopenia (63.1%), neutropenia (40%), diarrhea (20%), radiation dermatitis (15.4%), and febrile neutropenia (3.1%). Only 6 (9.2%) showed grade 3 late toxicities. No treatment-related deaths were observed. Conclusions: Although dCRT with S-1/MMC showed acceptable toxicities and favorable 3-year survival, this study did not meet its primary endpoint. Clinical trial information: UMIN000003237.