title: Taxanes versus S-1 as the first-line chemotherapy for metastatic breast cancer (SELECT BC): an open-label, non-inferiority, randomised phase 3 trial.
abstract: BACKGROUND
  Oral fluoropyrimidines are used for the first-line treatment of metastatic breast cancer to avoid severe adverse effects, although firm supporting evidence is lacking. We aimed to establish whether S-1 is non-inferior to taxanes in this setting.
  
  
  METHODS
  We did an open-label, non-inferiority, phase 3 trial at 154 hospitals in Japan. We enrolled individuals who had HER2-negative metastatic breast cancer who had received no chemotherapy for advanced disease, and who were resistant to endocrine treatment. Patients were randomly assigned (1:1) either to taxane (docetaxel 60-75 mg/m(2) at intervals of 3-4 weeks; paclitaxel 80-100 mg/m(2) weekly for 3 of 4 weeks; or paclitaxel 175 mg/m(2) at intervals of 3-4 weeks) or to S-1 (40-60 mg twice daily for 28 consecutive days, followed by a 14-day break). Randomisation was done centrally with the minimisation method, with stratification by institution, liver metastasis, oestrogen and progesterone receptor status, previous treatment with taxanes or oral fluorouracil, and time from surgery to recurrence. The primary endpoint was overall survival, with a prespecified non-inferiority margin of 1·333 for the hazard ratio (HR). The primary efficacy analysis was done in the full analysis set, which consisted of all patients who took at least one study treatment and who had all data after randomisation. This trial is registered with the University Hospital Medical Information Network, Japan (protocol ID C000000416).
  
  
  RESULTS
  Between Oct 27, 2006, and July 30, 2010, we enrolled 618 patients (309 assigned to taxane; 309 assigned to S-1). The full analysis set consisted of 286 patients in the taxane group and 306 in the S-1 group. Median follow-up was 34·6 months (IQR 17·9-44·4). Median overall survival was 35·0 months (95% CI 31·1-39·0) in the S-1 group and 37·2 months (33·0-40·1) in the taxane group (HR 1·05 [95% CI 0·86-1·27]; pnon-inferiority=0·015). The most common grade 3 or worse adverse events were neutropenia (20 [7%] of 307 patients in the S-1 group vs nine [3%] of 290 patients in the taxane group), fatigue (ten [3%] vs 12 [4%]), and oedema (one [<1%] vs 12 [4%]). Treatment-related deaths were reported in two patients in the taxane group.
  
  
  CONCLUSIONS
  S-1 is non-inferior to taxane with respect to overall survival as a first-line treatment for metastatic breast cancer. S-1 should be considered a new option for first-line chemotherapy for patients with HER2-negative metastatic breast cancer.
  
  
  BACKGROUND
  Comprehensive Support Project for Oncology Research of the Public Health Research Foundation, Japan; Taiho.
authors.affiliation: Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Takashima
authors.affiliation: National Cancer Center Hospital East, Kashiwa, Japan. Electronic address: hrmukai@east.ncc.go.jp.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Mukai
authors.affiliation: National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.
authors.forename: Fumikata
authors.initials: F
authors.lastname: Hara
authors.affiliation: National Cancer Center Hospital East, Kashiwa, Japan.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Matsubara
authors.affiliation: Saitama Red Cross Hospital, Saitama, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Saito
authors.affiliation: Toranomon Hospital, Tokyo, Japan.
authors.forename: Toshimi
authors.initials: T
authors.lastname: Takano
authors.affiliation: Tohoku Pharmaceutical University Hospital, Sendai, Japan.
authors.forename: Youngjin
authors.initials: Y
authors.lastname: Park
authors.affiliation: Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Toyama
authors.affiliation: Jichi Medical University, Tochigi, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Hozumi
authors.affiliation: Kinki University Faculty of Medicine, Osakasayama, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Tsurutani
authors.affiliation: School of Medicine Kyorin University, Mitaka, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Imoto
authors.affiliation: National Hospital Organization Sendai Medical Center, Sendai, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Hakuaikai Medical Corp Sagara Hospital, Kagoshima, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Sagara
authors.affiliation: Kumamoto Shinto General Hospital, Kumamoto, Japan.
authors.forename: Reiki
authors.initials: R
authors.lastname: Nishimura
authors.affiliation: Ritsumeikan University, Kusatsu, Japan.
authors.forename: Kojiro
authors.initials: K
authors.lastname: Shimozuma
authors.affiliation: Chuo University, Tokyo, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ohashi
mesh_terms: D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology* / Q000601:surgery; D018450:Disease Progression; D018572:Disease-Free Survival; D000077143:Docetaxel; D004338:Drug Combinations; D004487:Edema / Q000139:chemically induced; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005500:Follow-Up Studies; D006304:Health Status; D006801:Humans; D008113:Liver Neoplasms / Q000556:secondary*; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D010094:Oxonic Acid / Q000009:adverse effects / Q000627:therapeutic use*; D017239:Paclitaxel / Q000009:adverse effects / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis; D015996:Survival Rate; D043823:Taxoids / Q000009:adverse effects / Q000627:therapeutic use*; D005641:Tegafur / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D000077143:Docetaxel; D004338:Drug Combinations; D010094:Oxonic Acid; D017239:Paclitaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D043823:Taxoids; D005641:Tegafur; C079198:S 1 (combination); C508053:ERBB2 protein, human