title: Paclitaxel plus valproic acid versus paclitaxel alone as second- or third-line therapy for advanced gastric cancer: a randomized Phase II trial.
abstract: BACKGROUND
  Weekly paclitaxel (wPTX) is the preferred second-line chemotherapy for gastric cancer in Japan. Histone deacetylase inhibitors have been shown to decrease proliferation through cell-cycle arrest, differentiation, and apoptosis in gastric cancer cells. One histone deacetylase inhibitor, valproic acid (VPA), also inhibits tumor growth by inducing apoptosis and enhances the efficacy of paclitaxel (PTX), shown in a murine gastric cancer model. This Phase II trial was designed to evaluate the benefits of adding VPA to wPTX in patients with gastric cancer refractory to first-line treatment with fluoropyrimidine.
  
  
  METHODS
  The patients were randomly assigned in a 1:1 ratio to receive PTX 80 mg/m(2) intravenously on days 1, 8, and 15, every 4 weeks, or a dose of PTX plus VPA taken everyday at 7.5 mg/kg twice daily. Random assignment was carried out at the data center with a minimization method adjusted by the Eastern Cooperative Oncology Group performance status (0-1 vs 2), prior chemotherapy (first-line vs second-line), and measurable lesions (presence vs absence). The primary end point was the overall survival (OS) rate, and the secondary end points were the progression-free survival rate and safety analysis.
  
  
  RESULTS
  Sixty-six patients were randomly assigned to receive wPTX (n=33) or wPTX plus VPA (n=33). The median OS was 9.8 months in the wPTX group and 8.7 months in the wPTX plus VPA group (hazard ratio 1.19; 95% CI 0.702-2.026; P=0.51). The median progression-free survival was 4.5 months in the wPTX group and 3.0 months in the wPTX plus VPA group (hazard ratio 1.29; 95% CI 0.753-2.211; P=0.35). Grade 3-4 adverse events were neutropenia (3.1%), pneumonia (1.6%), liver injury (1.6%), brain infarction (1.6%), and rupture of aorta (1.6%).
  
  
  CONCLUSIONS
  No statistically significant difference was observed between wPTX and wPTX plus VPA for OS.
authors.affiliation: Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa.
authors.forename: Sachio
authors.initials: S
authors.lastname: Fushida
authors.affiliation: Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa.
authors.forename: Jun
authors.initials: J
authors.lastname: Kinoshita
authors.affiliation: Department of Surgery, Toyama Prefectural Central Hospital, Toyama.
authors.forename: Masahide
authors.initials: M
authors.lastname: Kaji
authors.affiliation: Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa.
authors.forename: Katsunobu
authors.initials: K
authors.lastname: Oyama
authors.affiliation: First Department of Surgery, Fukui University Hospital, Fukui.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Hirono
authors.affiliation: Department of Surgery, Toyama Prefectural Central Hospital, Toyama.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Tsukada
authors.affiliation: Department of Surgery, Toyama City Hospital, Toyama, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujimura
authors.affiliation: Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ohta
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000737:chemistry / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D006801:Humans; D007564:Japan; D051379:Mice; D017239:Paclitaxel / Q000737:chemistry / Q000627:therapeutic use*; D013274:Stomach Neoplasms / Q000473:pathology*; D016896:Treatment Outcome; D014635:Valproic Acid / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D014635:Valproic Acid; D017239:Paclitaxel
keywords: advanced gastric cancer; paclitaxel; second- or third-line therapy; valproic acid