Addition of docetaxel to S-1 without platinum prolongs survival of patients with advanced gastric cancer: a randomized study (START)

Abstract

Purpose Cisplatin plus 5-fluorouracil has been globally accepted as a standard regimen for the treatment for advanced gastric cancer. However, cisplatin has several disadvantages, including renal toxicity and the need for admission. S-1 plus cisplatin has become a standard treatment for advanced gastric cancer in East Asia. This phase III study was designed to evaluate the potential benefits of adding docetaxel to S-1 without a platinum compound in patients with advanced gastric cancer.MethodsPatients were randomly assigned to receive docetaxel plus S-1 or S-1 alone. The docetaxel plus S-1 group received docetaxel on day 1 and oral S-1 on days 1–14 of a 21-day cycle. The S-1 alone group received oral S-1 on days 1–28 of a 42-day cycle. The primary end point was overall survival.ResultsOf the 639 patients enrolled, 635 were eligible for analysis. The median overall survival was 12.5 months in the docetaxel plus S-1 group and 10.8 months in the S-1 alone group (p = 0.032). The median progression-free survival was 5.3 months in the docetaxel plus S-1 group and 4.2 months in the S-1 alone group (p = 0.001). As for adverse events, neutropenia was more frequent in the docetaxel plus S-1 group, but remained manageable.ConclusionAs first-line treatment for advanced gastric cancer, docetaxel plus S-1 significantly improves median overall and progression-free survival as compared with S-1 alone. (ClinicalTrials.gov number: NCT00287768).

A phase II study of perioperative S-1 combined with weekly docetaxel in patients with locally advanced gastric carcinoma: clinical outcomes and clinicopathological and pharmacogenetic predictors for survival

“…In addition, 7 of 47 patients (15 %) in their study did not complete neoadjuvant chemotherapy because of adverse events. A recent phase III trial with first-line S-1 plus docetaxel in advanced GC, in which both agents were also administered at lower doses compared to our regimen, reported a response rate of 38.8 %, which was lower than 66.7 % in our previous study for metastatic GC [13,29].…”

5FU resistance caused by reduced fluoro-deoxyuridine monophosphate and its reversal using deoxyuridine

“…5FU is currently a key drug for adjuvant therapy following curative surgery (2)(3)(4) and for the treatment of metastatic gastric cancer (5,6). Three mechanisms have been proposed for its action: Incorporation into RNA (7), incorporation into DNA (8) and the inhibition of thymidine synthase (TS) leading to the inhibition of DNA de novo synthesis by forming a ternary complex composed of TS, 5,10-methylenetetrahydrofolate (CH2THF) and fluoro-deoxyuridine monophosphate (FdUMP) (9).…”

2300 A multicenter randomized phase II study of docetaxel vs. docetaxel plus cisplatin vs. docetaxel plus S-1 as second-line chemotherapy in metastatic gastric cancer patients who had progressed after cisplatin plus either S-1 or capecitabine

“…Based on the safety and efficacy of these trials, the dose in the docetaxel plus cisplatin arm was determined to be 60 mg/m 2 each for the current trial. In the docetaxel plus S-1 arm, although the recommended doses of triweekly S-1 plus docetaxel were S-1 80 mg/m 2 /day on days 1 to 14 and docetaxel 40 mg/m 2 on day 1 in previous studies [21,22], this study used the same dose of docetaxel (60 mg/m 2 ) as in the docetaxel plus cisplatin arm, along with a reduced dose of S-1 (60 mg/m 2 /day). Randomization was performed using the random permutation method to stratify the patients according to the study site, ECOG performance status (0-1 vs. 2), and the best response to first-line chemotherapy (complete or partial response vs. stable disease or progressive disease).…”