The phase I trial of preoperative short-course chemoradiotherapy with S-1/irinotecan and short-course radiation in locally advanced lower rectal cancer (SHOWTIME study)

A phase I study was conducted to determine the optimal dose of irinotecan in short-course chemoradiotherapy (SCCRT) using S-1/irinotecan and short-course radiotherapy (SCRT) for the development of a new total neoadjuvant therapy (TNT) regimen that is safe, effective, and has a low patient burden for locally advanced rectal cancer (LARC).

The objective of this study was to ascertain the maximum tolerated dose (MTD) and the recommended dose (RD) of irinotecan in SCCRT for locally advanced rectal cancer. The assessment of dose-limiting toxicity (DLT) was conducted over a 14-day period following treatment administration. The patient received a 14-day course of chemotherapy, with S-1 administered from the first to the fifth day and from the eighth to the twelfth day. Irinotecan was administered on the first and eighth days of treatment. The radiotherapy regimen was initiated with a total dose of 25 Gy, administered in five fractions from the eighth to twelfth day.

Fifteen patients received SCRT in conjunction with S-1 and escalating doses of irinotecan (40–60 mg/m²). All patients completed the SCCRT protocol. At a dose of 60 mg/m², DLT occurred in all patients, thereby establishing this dosage as the MTD. At a dose of 50 mg/m², DLT was observed in two of six patients, thereby establishing this dose as the RD. The most prevalent Grade ≥ 3 adverse event was diarrhea. All patients received CapeOX-based consolidation chemotherapy. Among the 11 surgical cases, the R0 resection rate was 100%, with a pathological complete response in 27.3% and downstaging in 90.9%. Three patients demonstrated a complete clinical response and underwent non-operative management.

The safety and feasibility of administering SCCRT with S-1/irinotecan at a 50 mg/m² irinotecan dose have been demonstrated. These findings support further investigation of this regimen in a TNT setting for rectal cancer.

The present study was duly registered with the Japan Clinical Trials Registry (jRCT s031210461). URL: https://jrct.mhlw.go.jp/re.