Elsevier

The Lancet Oncology

Volume 15, Issue 8, July 2014, Pages 886-893
The Lancet Oncology

Articles
Sequential paclitaxel followed by tegafur and uracil (UFT) or S-1 versus UFT or S-1 monotherapy as adjuvant chemotherapy for T4a/b gastric cancer (SAMIT): a phase 3 factorial randomised controlled trial

https://doi.org/10.1016/S1470-2045(14)70025-7Get rights and content

Summary

Background

The prognosis for locally advanced gastric cancer is poor despite advances in adjuvant chemotherapy. We did the Stomach cancer Adjuvant Multi-Institutional group Trial (SAMIT) to assess the superiority of sequential treatment (paclitaxel then tegafur and uracil [UFT] or paclitaxel then S-1) compared with monotherapy (UFT or S-1) and also the non-inferiority of UFT compared with S-1.

Methods

We did this randomised phase 3 trial with a two-by-two factorial design at 230 hospitals in Japan. We enrolled patients aged 20–80 years with T4a or T4b gastric cancer, who had had D2 dissection and a ECOG performance score of 0–1. Patients were randomly assigned to one of four treatment groups with minimisation for tumour size, lymph node metastasis, and study site. Patients received UFT only (267 mg/m2 per day), S-1 only (80 mg/m2 per day) for 14 days, with a 7-day rest period or three courses of intermittent weekly paclitaxel (80 mg/m2) followed by either UFT, or S-1. Treatment lasted 48 weeks in monotherapy groups and 49 weeks in the sequential treatment groups. The primary endpoint was disease-free survival assessed by intention to treat. We assessed whether UFT was non-inferior to S-1 with a non-inferiority margin of 1·33. This trial was registered at UMIN Clinical Trials Registry, number C000000082.

Findings

We randomly assigned 1495 patients between Aug 3, 2004, and Sept 29, 2009. 374 patients were assigned to receive UFT alone, 374 to receive S-1 alone, 374 to received paclitaxel then UFT, and 373 to receive paclitaxel then S-1. We included 1433 patients in the primary analysis after at least 3 years of follow-up (359, 364, 355, and 355 in each group respectively). Protocol treatment was completed by 215 (60%) patients in the UFT group, 224 (62%) in the S-1 group, 242 (68%) in the paclitaxel then UFT group, and 250 (70%) in the paclitaxel then S-1 group. 3-year disease-free survival for monotherapy was 54·0% (95% CI 50·2–57·6) and that of sequential treatment was 57·2% (53·4–60·8; hazard ratio [HR] 0·92, 95% CI 0·80–1·07, p=0·273). 3-year disease-free survival for the UFT group was 53·0% (95% CI 49·2–56·6) and that of the S-1 group was 58·2% (54·4–61·8; HR 0·81, 95% CI 0·70–0·93, p=0·0048; pnon-inferiority=0·151). The most common grade 3–4 haematological adverse event was neutropenia (41 [11%] of 359 patients in the UFT group, 48 [13%] of 363 in the S-1 group, 46 [13%] of 355 in the paclitaxel then UFT group, and 83 [23%] of 356 in the paclitaxel then S-1 group). The most common grade 3–4 non-haematological adverse event was anorexia (21 [6%], 24 [7%], seven [2%], and 18 [5%], respectively).

Interpretation

Sequential treatment did not improve disease-free survival, and UFT was not non-inferior to S-1 (and S-1 was superior to UFT), therefore S-1 monotherapy should remain the standard treatment for locally advanced gastric cancer in Japan.

Funding

Epidemiological and Clinical Research Information Network.

Introduction

Gastric cancer is the fourth most common cancer worldwide and the second leading cause of cancer mortality.1 The prognosis of locally advanced tumours remains poor despite advances in adjuvant chemotherapy.2, 3, 4 More effective adjuvant chemotherapy treatments are needed for curatively resected but locally advanced gastric cancer.

Oral fluoropyrimidines and taxanes are often used to treat both gastric and breast cancer,5, 6, 7 and taxanes are important drugs for breast and ovarian cancer given singly or in combination.8, 9 Docetaxel provided modest but better survival than did paclitaxel every 3 weeks in a trial of advanced breast cancer; but its toxic effects were worse,10 and it has not been compared with dose-dense paclitaxel once per week, which is superior to paclitaxel every 3 weeks for ovarian cancer.9, 11 Sequential treatment with single taxanes is often preferred owing to fewer toxic effects and quality of life seems to be better.12, 13

Peritoneal metastasis are the most common site of relapse in patients with gastric cancer,3 for whom serosal exposure is a major risk.14, 15 Paclitaxel is effective for treatment of malignant ascites from gastric cancer,16 and in studies17, 18 of paclitaxel for the second-line chemotherapy, it was especially effective for peritoneal metastasis. Fluoropyrimidine monotherapy has been used for adjuvant chemotherapy in Asia, and a combination of tegafur and uracil (UFT) was for a time the Japanese community standard treatment for gastric cancer because of its efficacy, good compliance, and safety.5 In 2007, the NSAS-GC study19 showed that UFT plus surgery was more effective than surgery alone for Japanese patients who had had a D2 dissection for T2 and lymph node positive gastric cancer. UFT has since been replaced by S-1 in Japan because of the results of ACTS-GC,3 which was a large randomised controlled trial for stage II and III tumours, although no direct comparison of these two drugs has been done. Combination of paclitaxel and oral fluoropyrimidine is a candidate treatment for curatively resected gastric cancer at high risk of peritoneal recurrence (ie, serosa-positive tumours).14 However, no comparison has been done of concurrent and sequential regimens. Because of the poor nutrition of patients after gastrectomy20 and the interaction between paclitaxel and fluorouracil,21 we tested the effect of sequential paclitaxel followed by S-1 for locally advanced gastric cancer in the single group trial,22 with favourable results.

We did the Stomach cancer Adjuvant Multi-institutional group (SAMIT) trial for T4a or T4b23 gastric cancer to assess (1) the effect on survival of paclitaxel followed by oral fluoropyrimidine (sequential treatment) compared with fluoropyrimidine alone (monotherapy), and (2) the non-inferiority of UFT compared with S-1.24

Section snippets

Study design and participants

We did this phase 3, randomised controlled study at 230 hospitals in Japan. We used a two-by-two factorial design, with four treatment groups: UFT alone, S-1 alone, paclitaxel followed by UFT, and paclitaxel followed by S-1. This design enabled us to evaluate the superiority of sequential treatment compared with monotherapy as well as the non-inferiority of UFT compared with S-1. The design of the study has been described previously.24

Panel 1 shows the eligibility criteria. In the original

Results

Between Aug 3, 2004 and Sept 24, 2009, 1495 patients were randomly assigned to a treatment group (figure 1). 62 patients were excluded because of ineligibility (n=27), withdrawal of consent (n=25), or no data (n=10). 1368 (96%) patients were followed up. Baseline characteristics were well balanced between the four treatment groups (table 1). Full protocol treatment was completed by 215 (60%) of 359 patients in the UFT only group, 224 (62%) of 364 in the S-1 only group, 242 (68%) of 355 in the

Discussion

Sequential paclitaxel did not improve disease-free survival and UFT was not non-inferior to S-1; S-1 was superior to UFT as adjuvant treatment for T4a or T4b gastric cancer. These results suggest that S-1 monotherapy should remain the standard treatment for locally advanced gastric cancer in Japan.

To our knowledge, the SAMIT trial is the largest-ever adjuvant trial for gastric cancer. Few other large randomised adjuvant trials have been done for gastric cancer, especially after radical lymph

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