title: Randomized double-blinded, placebo-controlled phase II trial of simvastatin and gemcitabine in advanced pancreatic cancer patients.
abstract: BACKGROUND
  Statins have potential antineoplastic properties via arrest of cell-cycle progression and induction of apoptosis. A previous study demonstrated in vitro and in vivo antineoplastic synergism between statins and gemcitabine. The present randomized, double-blinded, phase II trial compared the efficacy and safety of gemcitabine plus simvastatin (GS) with those of gemcitabine plus placebo (GP) in patients with locally advanced and metastatic pancreatic cancer.
  
  
  METHODS
  Patients were randomly assigned to receive a 3-week regimen with GS (gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 plus simvastatin 40 mg once daily) or GP (gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 plus placebo). The primary end point was time to progression (TTP).
  
  
  RESULTS
  Between December 2008 and April 2012, 114 patients were enrolled. The median TTP was not significantly different between the two arms, being 2.4 months (95 % CI 0.7-4.1 months) and 3.6 months (95 % CI 3.1-4.1 months) in the GS and GP arms, respectively (P = 0.903). The overall disease control rate was 39.7 % (95 % CI 12.2-33.8 %) and 57.1 % (95 % CI 19.8-44.2 %) in the GS and GP arms, respectively (P = 0.09). The 1-year expected survival rates were similar (27.7 and 31.7 % in the GS and GP arms, respectively; P = 0.654). Occurrence of grade 3 or 4 adverse events was similar in both arms, and no patients had rhabdomyolysis.
  
  
  CONCLUSIONS
  Adding low-dose simvastatin to gemcitabine in advanced pancreatic cancer does not provide clinical benefit, although it also does not result in increased toxicity. Given the emerging role of statins in overcoming resistance to anti-EGFR treatment, further studies are justified to evaluate the efficacy and safety of combined simvastatin and anti-EGFR agents, such as erlotinib or cetuximab, plus gemcitabine for treating advanced pancreatic cancer.
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong Gangnam-gu, Seoul, 135-710, Korea.
authors.forename: Jung Yong
authors.initials: JY
authors.lastname: Hong
authors.forename: Eun Mi
authors.initials: EM
authors.lastname: Nam
authors.forename: Jeeyun
authors.initials: J
authors.lastname: Lee
authors.forename: Joon Oh
authors.initials: JO
authors.lastname: Park
authors.forename: Sang-Cheol
authors.initials: SC
authors.lastname: Lee
authors.forename: Seo-Young
authors.initials: SY
authors.lastname: Song
authors.forename: Seong Ho
authors.initials: SH
authors.lastname: Choi
authors.forename: Jin Seok
authors.initials: JS
authors.lastname: Heo
authors.forename: Se Hoon
authors.initials: SH
authors.lastname: Park
authors.forename: Ho Yeong
authors.initials: HY
authors.lastname: Lim
authors.forename: Won Ki
authors.initials: WK
authors.lastname: Kang
authors.forename: Young Suk
authors.initials: YS
authors.lastname: Park
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004311:Double-Blind Method; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000401:mortality; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D019821:Simvastatin / Q000008:administration & dosage*; D018631:ras Proteins / Q000235:genetics; D000093542:Gemcitabine
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D003841:Deoxycytidine; D019821:Simvastatin; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000093542:Gemcitabine