SAMIT: A phase III randomized clinical trial of adjuvant paclitaxel followed by oral fluorinated pyrimidines for locally advanced gastric cancer.

Abstract

LBA4002 Background: Adjuvant chemotherapy with tegafur/uracil (UFT) used to be a tentative Japanese standard treatment and has been replaced by S-1 according to the result of the ACTS-GC trial, although there has been no direct comparison. Paclitaxel (PTX) has been widely used as one of the key drugs for unresectable GC. A randomized phase III trial with a two-by-two factorial design was planned to assess the survival benefit of sequential use of PTX and oral fluorinated pyrimidines (FPs) in comparison with FPs alone, and to compare UFT and S-1. Methods: Patients with serosa-invading GC who underwent R0/1 resection with extended (D2) lymph node dissection were randomized to receive either UFT 267mg/m2 daily (arm A), S-1 80mg/m2 daily for 2 weeks every 3 weeks (B), weekly PTX 80 mg/m2 followed by UFT (C), or PTX followed by S-1 (D) for 24 weeks. The primary endpoint was disease-free survival (DFS). 708 patients per groups were necessary to detect a hazard ratio of 0.8 with 90% power for superiority of the sequential arms, C+D, vs. A+B (two-sided 5.0% significance level). The number of patients was set to 370 per arm (total 1480) with an 88% power for noninferiority (1.33 as the margin) of UFT vs. S-1. Results: Between August 2004 and October 2007, 1,495 patients from 232 centers were randomized with the full analysis set of 1,433. Demographics were well balanced among arm A (n=359), B (n=364), C (n=355), and D (n=355); mean age was 64, 86% were PS 0, 68% of tumors were 8 cm or greater and 85% were clinically node positive. Grade 3-4 neutropenia or anorexia occurred in 11% or 6%, 13% or 7%, 13% or 2%, and 23% or 5% for arm A, B, C, and D, respectively. Other % grade 3-4 toxicities were less than 5%. Median follow-up was 1,875 days and 728 events occurred. Difference in DFS between C+D and A+B were not statistically significant (HR=0.92, 95%CI 0.80-1.07, p= 0.273). HR of A+C vs. B+D was 1.23 (95%CI 1.07-1.43) and hence the null hypothesis was not rejected. Conclusions: There was a trend for better DFS for sequential use of PTX followed by FPs. Comparison between the FPs demonstrated that UFT was inferior to S-1. Sequential PTX/S-1 is safe and effective for locally advanced GC in an adjuvant setting. Clinical trial information: C000000082.