A phase I/II study of S-1 plus oxaliplatin combined with radiation (SOX/RT) for preoperative locally advanced rectal carcinoma (JACCRO CC-04: SHOGUN trial).

Abstract

602 Background: Previous western trials of preoperative chemoradiation (CRT) in patients with locally advanced rectal carcinoma (LARC) have been shown to increase the chance of sphincter preservation and local control, and has become the standard of care in western countries. In Japan, preoperative CRT has not been utilized in LARC and its value is unconfirmed. Thus, we conducted a phase I/II study of preoperative CRT with S-1, which is widely used oral fluoropyrimidine in Japan to treat gastrointestinal cancer, plus oxaliplatin in patients with LARC. Methods: Patients with histopathologically confirmed LARC (cT3-T4, any N) were eligible. A total radiation dose of 50.4 Gy was delivered in 28 fractions over 5 weeks, and S-1 was orally administered 40mg/m2 twice a day for 5 days a week at 1st, 2nd, 4th and 5th week. Oxaliplatin was administered at a dose of 40 mg/m2 (level 1), 50 mg/m2 (level 2) or 60 mg/m2(level 3) on day 1, 8, 22 and 29. Surgery was performed within 6-10 weeks after CRT. The primary endpoint of phase I part was to determine the maximum tolerated dose (MTD) and the recommended dose (RD) of oxaliplatin. Primary endpoint of phase II was evaluated pathologic complete response (pCR) rate at RD. Results: 13 patients were enrolled in the phase I part, 2 dose-limiting toxicities (DLTs, skipping oxaliplatin due to the grade 2 neutropenia) occurred in the dose level 3, and the MTD was not reached. In phase II, 45 patients were treated at the RD of oxaliplatin (60 mg/m2) and 44 patients (97.8%) underwent surgery. A pCR was observed in 12 patients (27.3%). The relative dose intensity of radiation, S-1, oxaliplatin was 98.4%, 94.0%, and 94.3%, respectively. The incidence of grade 3-4 diarrhea and neutropenia was 8.9% and 2.2%, respectively. Postoperative complications of any grade occurred in 27.3% of patients. Conclusions: Preoperative CRT with S-1 plus oxaliplatin showed promising results in pathological responses and favorable toxicities profiles. Clinical trial information: NCT01227239.