title: Simvastatin plus capecitabine-cisplatin versus placebo plus capecitabine-cisplatin in patients with previously untreated advanced gastric cancer: a double-blind randomised phase 3 study.
abstract: OBJECTIVE
  We aimed to the addition of synthetic 3-hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase inhibitor, simvastatin to capecitabine-cisplatin (XP) in patients with previously untreated advanced gastric cancer (AGC).
  
  
  METHODS
  In this double-blind, placebo-controlled, phase III study, we enrolled patients aged 18 years or older with histological or cytological confirmed metastatic adenocarcinoma of the stomach or gastroesophageal junction (GEJ) at nine centres in Korea. Patients, stratified by disease measurability and participating site, were randomly assigned (1:1) to receive capecitabine 1000mg/m(2) twice daily for 14 days and cisplatin 80 mg/m(2) on day 1 every 3 weeks plus either simvastatin 40 mg or placebo, once daily. Cisplatin was given for 8 cycles; capecitabine and simvastatin were administered until disease progression or unacceptable toxicities. This study is registered with ClinicalTrials.gov, number NCT01099085.
  
  
  RESULTS
  Between February 2009 and November 2012, 244 patients were enrolled and assigned to treatment groups (120 simvastatin, 124 placebo). Median progression free survival (PFS) for 120 patients allocated XP plus simvastatin was 5.2 months (95% confidence interval (CI) 4.3-6.1) compared with 4.63 months (95% CI 3.5-5.7) for 124 patients who were allocated to XP plus placebo (hazard ratio 0.930, 95% CI 0.684-1.264; p=0.642). 63 (52.5%) of 120 patients in simvastatin group and 70 (56.4%) of 124 had grade 3 or higher adverse events.
  
  
  CONCLUSIONS
  Addition of 40 mg simvastatin to XP does not increase PFS in our trial, although it does not increase toxicity. Low dose of simvastatin (40 mg) to chemotherapy is not recommended in untargeted population with AGC.
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Seung Tae
authors.initials: ST
authors.lastname: Kim
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, College of Medicine, Gyeongsang National University, Jinju, South Korea.
authors.forename: Jung Hun
authors.initials: JH
authors.lastname: Kang
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Jeeyun
authors.initials: J
authors.lastname: Lee
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Se Hoon
authors.initials: SH
authors.lastname: Park
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Joon Oh
authors.initials: JO
authors.lastname: Park
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Young Suk
authors.initials: YS
authors.lastname: Park
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Ho Yeong
authors.initials: HY
authors.lastname: Lim
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, College of Medicine, Chung-Ang University, Seoul, South Korea.
authors.forename: In Gyu
authors.initials: IG
authors.lastname: Hwang
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, College of Medicine, Soonchunhyang University, Cheonan, South Korea.
authors.forename: Sang-Cheol
authors.initials: SC
authors.lastname: Lee
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, College of Medicine, Dankook University, Cheonan, South Korea.
authors.forename: Keon-Woo
authors.initials: KW
authors.lastname: Park
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Korea Cancer Center Hospital, Seoul, South Korea.
authors.forename: Hyo Rak
authors.initials: HR
authors.lastname: Lee
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. Electronic address: wkkang@skku.edu.
authors.forename: Won Ki
authors.initials: WK
authors.lastname: Kang
mesh_terms: D000214:Acyl Coenzyme A / Q000037:antagonists & inhibitors; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000069287:Capecitabine; D002945:Cisplatin / Q000008:administration & dosage*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D019821:Simvastatin / Q000008:administration & dosage*; D013274:Stomach Neoplasms / Q000188:drug therapy*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000214:Acyl Coenzyme A; D003841:Deoxycytidine; C008047:3-hydroxy-3-methylglutaryl-coenzyme A; D000069287:Capecitabine; D019821:Simvastatin; D002945:Cisplatin; D005472:Fluorouracil
keywords: Gastric cancer; Simvastatin; Synthetic 3-hydroxy-3-methyglutaryl coenzyme A (HMG-CoA)