Final analysis of dose-finding and single-arm confirmatory study (phase I/II 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.
Authors: Yoshinori Ito, Tetsuya Hamaguchi, Atsuo Takashima, Junki Mizusawa, Yasuhiro Shimada, Manabu Shiozawa, Takeshi Kodaira, Masayuki Ohue, Makoto Kinouchi, Kohei Murata, Gen Iinuma, Fumihiko Fujita, Hirohisa Miura, Fumio Ishida, Yoshihisa Saida, Takahisa Matsuda, Hiroshi Katayama, Haruhiko Fukuda, Yukihide Kanemitsu
Journal: Journal of Clinical Oncology (2021)

3521 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 dose-finding (phase I) part and to evaluate the efficacy and safety in confirmatory (phase II) part for cStage II/III SCCA. We reported the RD of S-1 and the 3-year survival at 2019 Gastrointestinal Cancers Symposium. We report the final data after 5-year follow-up. 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/m 2 on days 1, 29) and S-1 (60 mg/m 2 /d in level 0 and 80 mg/m 2 /d in level 1 on days 1-14, 29-42) with concurrent radiotherapy of 59.4 Gy/33fr. The dose-finding part adopted the 3+3 cohort design. The primary endpoint of confirmatory part was 3-year event-free survival (EFS). The sample size was 65 in the confirmatory part, with one-sided alpha of 5% and power of 80%, threshold and expected 3-year EFS as 60% and 75%. Key secondary endpoints were overall survival (OS) and progression-free survival (PFS) and colostomy-free survival (CFS), and adverse events. Final analysis was planned after 5-year follow-up for all pts. Results: From Feb/2010 to Mar/2015, 69 pts (3 in level 0 and 66 [7 in phase I and 59 in phase II] in level 1) were enrolled. Pts characteristics 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 dose-finding part, RD of S-1 was determined as 80 mg/m 2 /d. The complete response rate was 81% (95% CI, 69.1-90.0%) on central review. With a median follow-up of 5.4 years, 3- and 5-year EFS was 65.0% (90% CI 54.1-73.9%) and 63.4% (95% CI 50.2-73.9%). 5-year OS, PFS, and CFS were 84.1% (95% CI 72.5-91.1%), 84.1% (95% CI 72.4-91.1%), and 73.0% (95% CI 60.2-82.3%), respectively. In a univariable analysis, male sex (p = 0.045) prognosticated for poor OS and cT3 or T4 (p = 0.001), male sex (p = 0.019) and, PS 1 (p = 0.048) prognosticated for poor CFS. Nine (14.3%) of 63 pts at a dose level 1 developed recurrence or disease progression. Locoregional recurrence only and distant metastasis were observed in 1 pts (1.6%) and 8 pts (12.7%) respectively. Among all treated 65 pts, only 5 pts (7.7%) showed grade 3 late toxicities including jejunum obstruction, jejunum ulcer, proctitis, lower gastrointestinal hemorrhage, anal pain, radiation dermatitis, and ureteral stenosis. No Grade 4 or 5 late toxicities were observed. Conclusions: dCRT with S-1/MMC showed acceptable toxicities and favorable 5-year survival and could be a possible treatment option for pts with locally advanced SCCA. Clinical trial information: jRCTs031180002.