title: A KRAS mutation status-stratified randomized phase II trial of gemcitabine and oxaliplatin alone or in combination with cetuximab in advanced biliary tract cancer.
abstract: BACKGROUND
  Previous clinical trials have not proved that adding epidermal growth factor receptor inhibitors to chemotherapy confers a survival benefit for patients with advanced biliary tract cancer (ABTC). Whether the KRAS mutation status of tumor cells confounded the results of past studies is unknown.
  
  
  METHODS
  ABTC patients stratified by KRAS status, Eastern Cooperative Oncology Group performance status, and primary tumor location were randomized 1 : 1 to receive GEMOX (800 mg/m(2) gemcitabine and 85 mg/m(2) oxaliplatin) or C-GEMOX (500 mg/m(2) cetuximab plus GEMOX) every 2 weeks. The primary end point was objective response rate (ORR).
  
  
  RESULTS
  The study enrolled 122 patients between December 2010 and May 2012 (62 treated with C-GEMOX and 60 with GEMOX). Compared with GEMOX alone, C-GEMOX was associated with trend to better ORR (27% versus 15%; P = 0.12) and progression-free survival (PFS, 6.7 versus 4.1 months; P = 0.05), but not overall survival (OS, 10.6 versus 9.8 months; P = 0.91). KRAS mutations, which were detected in 36% of tumor samples, did not affect the trends of difference in ORR and PFS between C-GEMOX and GEMOX. The two treatment arms had similar adverse events, except that more patients had skin rashes, allergic reactions, and neutropenia in the C-GEMOX arm. Of patients with C-GEMOX, the presence of a grade 2 or 3 skin rash was associated with significantly better ORR, PFS, and OS.
  
  
  CONCLUSIONS
  Addition of cetuximab did not significantly improve the ORR of GEMOX chemotherapy in ABTC, although a trend of PFS improvement was observed. The trend of improvement did not correlate with KRAS mutation status.
  
  
  BACKGROUND
  This study is registered at ClinicalTrials.gov (NCT01267344). All patients gave written informed consent.
authors: on behalf of the Taiwan Cooperative Oncology Group Division of Hematology and Oncology, Department of Internal Medicine, Linkou Chang Gung Memorial Hospital and Chang Gung University, Taoyuan.
authors: J S
authors: JS
authors: Chen
authors: Department of Oncology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei.
authors: C
authors: C
authors: Hsu
authors: National Institute of Cancer Research, National Health Research Institutes, Tainan; Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan; Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung.
authors: N J
authors: NJ
authors: Chiang
authors: Division of Hematology and Oncology, Department of Internal Medicine, Tainan Municipal Hospital, Tainan.
authors: C S
authors: CS
authors: Tsai
authors: Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Miaoli.
authors: H H
authors: HH
authors: Tsou
authors: Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli.
authors: S F
authors: SF
authors: Huang
authors: Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung.
authors: L Y
authors: LY
authors: Bai
authors: Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli.
authors: I C
authors: IC
authors: Chang
authors: Taipei Cancer Center, Taipei Medical University Hospital, Taipei.
authors: H S
authors: HS
authors: Shiah
authors: Division of Hematology and Oncology, Department of Internal Medicine, Tri-Service General Hospital, Taipei.
authors: C L
authors: CL
authors: Ho
authors: Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan.
authors: C J
authors: CJ
authors: Yen
authors: Division of Hematology and Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chiayi.
authors: K D
authors: KD
authors: Lee
authors: Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung.
authors: C F
authors: CF
authors: Chiu
authors: Division of Hematology and Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung.
authors: K M
authors: KM
authors: Rau
authors: Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung.
authors: M S
authors: MS
authors: Yu
authors: Division of Hematology and Oncology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung.
authors: Y
authors: Y
authors: Yang
authors: Division of Hematology and Oncology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei.
authors: R K
authors: RK
authors: Hsieh
authors: National Institute of Cancer Research, National Health Research Institutes, Tainan; Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan.
authors: J Y
authors: JY
authors: Chang
authors: Department of Surgery, National Cheng Kung University Hospital, Tainan.
authors: Y S
authors: YS
authors: Shan
authors: Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan.
authors: Y
authors: Y
authors: Chao
authors: National Institute of Cancer Research, National Health Research Institutes, Tainan; Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan; Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung. Electronic address: leochen@nhri.org.tw.
authors: L T
authors: LT
authors: Chen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001661:Biliary Tract Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D000068818:Cetuximab / Q000008:administration & dosage* / Q000009:adverse effects; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009944:Organoplatinum Compounds / Q000009:adverse effects / Q000627:therapeutic use; D010641:Phenotype; D016016:Proportional Hazards Models; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D013624:Taiwan; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: C117307:KRAS protein, human; D009944:Organoplatinum Compounds; D003841:Deoxycytidine; D016283:Proto-Oncogene Proteins p21(ras); D000068818:Cetuximab
keywords: KRAS mutation; biliary tract cancer; cetuximab; chemotherapy