title: S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial.
abstract: BACKGROUND
  Phase I/II clinical trials of S-1 plus cisplatin for advanced gastric cancer have yielded good responses and the treatment was well tolerated. In this S-1 Plus cisplatin versus S-1 In RCT In the Treatment for Stomach cancer (SPIRITS) trial, we aimed to verify that overall survival was better in patients with advanced gastric cancer treated with S-1 plus cisplatin than with S-1 alone.
  
  
  METHODS
  In this phase III trial, chemotherapy-naive patients with advanced gastric cancer were enrolled between March 26, 2002, and Nov 30, 2004, at 38 centres in Japan, and randomly assigned to S-1 plus cisplatin or S-1 alone. In patients assigned to S-1 plus cisplatin, S-1 (40-60 mg depending on patient's body surface area) was given orally, twice daily for 3 consecutive weeks, and 60 mg/m(2) cisplatin was given intravenously on day 8, followed by a 2-week rest period, within a 5-week cycle. Those assigned to S-1 alone received the same dose of S-1 twice daily for 4 consecutive weeks, followed by a 2-week rest period, within a 6-week cycle. The primary endpoint was overall survival. Secondary endpoints were progression-free survival, proportions of responders, and safety. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00150670.
  
  
  RESULTS
  305 patients were enrolled; seven patients were ineligible or withdrew consent, therefore, 148 patients were assigned to S-1 plus cisplatin and 150 patients were assigned to S-1 alone. Median overall survival was significantly longer in patients assigned to S-1 plus cisplatin (13.0 months [IQR 7.6-21.9]) than in those assigned to S-1 alone (11.0 months [5.6-19.8]; hazard ratio for death, 0.77; 95% CI 0.61-0.98; p=0.04). Progression-free survival was significantly longer in patients assigned to S-1 plus cisplatin than in those assigned to S-1 alone (median progression-free survival 6.0 months [3.3-12.9] vs 4.0 months [2.1-6.8]; p<0.0001). Additionally, of 87 patients assigned S-1 plus cisplatin who had target tumours, one patient had a complete response and 46 patients had partial responses, ie, a total of 54% (range 43-65). Of 106 patients assigned S-1 alone who had target tumours, one patient had a complete response and 32 had partial responses, ie, a total of 31% (23-41). We recorded more grade 3 or 4 adverse events including leucopenia, neutropenia, anaemia, nausea, and anorexia, in the group assigned to S-1 plus cisplatin than in the group assigned to S-1 alone. There were no treatment-related deaths in either group.
  
  
  CONCLUSIONS
  S-1 plus cisplatin holds promise of becoming a standard first-line treatment for patients with advanced gastric cancer.
authors.affiliation: Kitasato University School of Medicine, Sagamihara, Japan. koizumi@med.kitasato-u.ac.jp
authors.forename: Wasaburo
authors.initials: W
authors.lastname: Koizumi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Narahara
authors.forename: Takuo
authors.initials: T
authors.lastname: Hara
authors.forename: Akinori
authors.initials: A
authors.lastname: Takagane
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Akiya
authors.forename: Masakazu
authors.initials: M
authors.lastname: Takagi
authors.forename: Kosei
authors.initials: K
authors.lastname: Miyashita
authors.forename: Takashi
authors.initials: T
authors.lastname: Nishizaki
authors.forename: Osamu
authors.initials: O
authors.lastname: Kobayashi
authors.forename: Wataru
authors.initials: W
authors.lastname: Takiyama
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Toh
authors.forename: Takashi
authors.initials: T
authors.lastname: Nagaie
authors.forename: Seiichi
authors.initials: S
authors.lastname: Takagi
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Yamamura
authors.forename: Kimihiko
authors.initials: K
authors.lastname: Yanaoka
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Orita
authors.forename: Masahiro
authors.initials: M
authors.lastname: Takeuchi
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D010094:Oxonic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000401:mortality; D015996:Survival Rate; D005641:Tegafur / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D004338:Drug Combinations; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D002945:Cisplatin