title: S-1 plus leucovorin versus S-1 plus leucovorin and oxaliplatin versus S-1 plus cisplatin in patients with advanced gastric cancer: a randomised, multicentre, open-label, phase 2 trial.
abstract: BACKGROUND
  Although leucovorin enhances the efficacy of fluorouracil, the anti-tumour activity of S-1 and leucovorin and their combination with oxaliplatin for patients with advanced gastric cancer is unknown. We compared the activity and safety of S-1 plus leucovorin, S-1 plus leucovorin and oxaliplatin, and S-1 plus cisplatin as first-line chemotherapy for advanced gastric cancer.
  
  
  METHODS
  In this multicentre, randomised, open-label, phase 2 trial, we recruited chemotherapy-naive patients with unresectable or recurrent gastric cancer with measurable lesions aged 20 years or older from 25 general hospitals and specialist centres in Japan. Patients were randomly assigned (1:1:1) centrally to receive S-1 plus leucovorin (S-1 40-60 mg orally plus oral leucovorin 25 mg twice a day for 1 week, every 2 weeks), S-1 plus leucovorin and oxaliplatin (S-1 plus leucovorin and intravenous oxaliplatin 85 mg/m(2) on day 1, every 2 weeks), or S-1 plus cisplatin (S-1 40-60 mg orally twice a day for 3 weeks, plus intravenous cisplatin 60 mg/m(2) on day 8, every 5 weeks). Randomisation was done with the minimisation method using performance status (0 vs 1) and tumour stage (stage IV vs recurrent) as stratification factors. The primary endpoint was independently reviewed overall response in the full analysis set. This trial is registered with Japic CTI, number 111635.
  
  
  RESULTS
  Between Oct 20, 2011, and Dec 17, 2012, we enrolled and randomly assigned 145 patients: 49 patients were assigned to S-1 plus leucovorin, 47 to S-1 plus leucovorin and oxaliplatin, and 49 to S-1 plus cisplatin. An objective response assessed by the independent review committee was achieved in 20 (43% [95% CI 28·3-57·8]) of the 47 patients in the S-1 plus leucovorin group, 31 (66% [50·7-79·1]) of the 47 patients in the S-1 plus leucovorin and oxaliplatin group, and 22 (46% [31·4-60·8]) of the 48 patients in the S-1 plus cisplatin group (Fisher's exact test, p=0·84 for S-1 plus leucovorin vs S-1 plus cisplatin, p=0·063 for S-1 plus leucovorin and oxaliplatin vs S-1 plus cisplatin, and p=0·038 for S-1 plus leucovorin and oxaliplatin vs S-1 plus leucovorin). The most common grade 3-4 adverse events were neutropenia (three [6%] of 48 patients in the S-1 plus leucovorin group vs 12 [26%] of 47 patients in the S-1 plus leucovorin and oxaliplatin group vs 17 [35%] of 49 patients in the S-1 plus cisplatin group), decreased appetite (six [13%] vs 14 [30%] vs 12 [24%]), anaemia (five [10%] vs seven [15%] vs 13 [27%]), and hyponatraemia (two [4%] vs two [4%] vs nine [18%]).
  
  
  CONCLUSIONS
  S-1 plus leucovorin and oxaliplatin was more active than S-1 plus leucovorin or S-1 plus cisplatin with acceptable toxic effects for patients with advanced gastric cancer. A phase 3 trial comparing S-1 plus leucovorin and oxaliplatin with S-1 plus cisplatin is underway.
  
  
  BACKGROUND
  Taiho Pharmaceutical.
authors.affiliation: Chiba Cancer Centre, Chiba, Japan. Electronic address: shironaka@ta2.so-net.ne.jp.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hironaka
authors.affiliation: Osaka Medical Centre for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors.forename: Naotoshi
authors.initials: N
authors.lastname: Sugimoto
authors.affiliation: Saitama Cancer Centre, Saitama, Japan.
authors.forename: Kensei
authors.initials: K
authors.lastname: Yamaguchi
authors.affiliation: University of Tsukuba, Tsukuba, Japan.
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Moriwaki
authors.affiliation: Hokkaido University, Sapporo, Japan.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Komatsu
authors.affiliation: National Hospital Organization Shikoku Cancer Centre, Matsuyama, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nishina
authors.affiliation: Kobe City Medical Centre General Hospital, Kobe, Japan.
authors.forename: Akihito
authors.initials: A
authors.lastname: Tsuji
authors.affiliation: St Marianna University School of Medicine, Kawasaki, Japan.
authors.forename: Takako Eguchi
authors.initials: TE
authors.lastname: Nakajima
authors.affiliation: Osaka Medical College Hospital, Takatsuki, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Gotoh
authors.affiliation: Shizuoka Cancer Centre, Shizuoka, Japan.
authors.forename: Nozomu
authors.initials: N
authors.lastname: Machida
authors.affiliation: National Cancer Centre Hospital East, Kashiwa, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Bando
authors.affiliation: National Hospital Organization Kyushu Cancer Centre, Fukuoka, Japan.
authors.forename: Taito
authors.initials: T
authors.lastname: Esaki
authors.affiliation: Saiseikai Fukuoka General Hospital, Fukuoka, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Emi
authors.affiliation: Showa University Northern Yokohama Hospital, Yokohama, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Sekikawa
authors.affiliation: Kyoto University Hospital, Kyoto, Japan.
authors.forename: Shigemi
authors.initials: S
authors.lastname: Matsumoto
authors.affiliation: Kitasato University School of Pharmacy, Tokyo, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Takeuchi
authors.affiliation: St Marianna University School of Medicine, Kawasaki, Japan.
authors.forename: Narikazu
authors.initials: N
authors.lastname: Boku
authors.affiliation: Kumamoto University, Kumamoto, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Baba
authors.affiliation: University of Tsukuba, Tsukuba, Japan.
authors.forename: Ichinosuke
authors.initials: I
authors.lastname: Hyodo
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000556:secondary; D000368:Aged; D000740:Anemia / Q000139:chemically induced; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage; D018572:Disease-Free Survival; D004338:Drug Combinations; D001068:Feeding and Eating Disorders / Q000139:chemically induced; D005260:Female; D006801:Humans; D007010:Hyponatremia / Q000139:chemically induced; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D010094:Oxonic Acid / Q000008:administration & dosage; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015996:Survival Rate; D005641:Tegafur / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D004338:Drug Combinations; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D002945:Cisplatin; D002955:Leucovorin