title: Phase II trial of S-1 plus leucovorin in patients with advanced gastric cancer and clinical prediction by S-1 pharmacogenetic pathway.
abstract: BACKGROUND
  The first one-arm phase II trial aimed to evaluate and predict efficacy and safety of S-1 plus oral leucovorin (S-1/LV) as first-line chemotherapy for patients with advanced gastric cancer (AGC), using S-1 pharmacogenetic pathway approach.
  
  
  METHODS
  A total of 39 patients orally took S-1 at conventional dose and LV simultaneously at a dose of 25 mg twice daily for a week, within a 2-week cycle. The primary endpoint was overall response rate (ORR), while the secondary endpoints were progression-free survival (PFS), time to failure (TTF), overall survival (OS), disease control rate (DCR), and adverse events (AEs). Peripheral blood was sampled prospectively for baseline expression of dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT), thymidine phosphorylase (TP), and thymidylate synthase (TS), CYP2A6 gene polymorphisms, and 5-FU pharmacokinetics.
  
  
  RESULTS
  The ORR and DCR were 41.0 and 76.9%. The median PFS, TTF, and OS were 4.13, 3.70, and 11.40 months. Grade 3-4 AEs occurred in only 13 patients, and grade 4 AEs occurred in only 1 of them. High OPRT/TS and peritoneal metastasis (vs. liver metastasis) independently predicted responding. High OPRT/DPD independently predicted grade 3-4 AEs. High AUC0-24hof 5-FU and metastatic/recurrent sites ≤2 (vs. >3) independently predicted prolonged PFS. Low baseline plasmic DPD independently predicted prolonged OS.
  
  
  CONCLUSIONS
  Two-week, oral S-1/LV regimen demonstrated promising efficacy and safety as first-line chemotherapy for AGC. CLINICALTRIALS.
  NCT02090153.
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dong Feng Road East, Guangzhou, 510060, China.
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: He
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dong Feng Road East, Guangzhou, 510060, China.
authors.forename: Dong-Sheng
authors.initials: DS
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dong Feng Road East, Guangzhou, 510060, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dong Feng Road East, Guangzhou, 510060, China.
authors.forename: Zi-Xian
authors.initials: ZX
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dong Feng Road East, Guangzhou, 510060, China.
authors.forename: Shu-Qiang
authors.initials: SQ
authors.lastname: Yuan
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dong Feng Road East, Guangzhou, 510060, China.
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dong Feng Road East, Guangzhou, 510060, China.
authors.forename: Hui-Yan
authors.initials: HY
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dong Feng Road East, Guangzhou, 510060, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Ren
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dong Feng Road East, Guangzhou, 510060, China.
authors.forename: Miao-Zhen
authors.initials: MZ
authors.lastname: Qiu
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dong Feng Road East, Guangzhou, 510060, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dong Feng Road East, Guangzhou, 510060, China.
authors.forename: De-Shen
authors.initials: DS
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dong Feng Road East, Guangzhou, 510060, China.
authors.forename: Dong-Liang
authors.initials: DL
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dong Feng Road East, Guangzhou, 510060, China.
authors.forename: Zhao-Lei
authors.initials: ZL
authors.lastname: Zeng
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dong Feng Road East, Guangzhou, 510060, China.
authors.forename: Yu-Hong
authors.initials: YH
authors.lastname: Li
authors.affiliation: Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
authors.forename: Yang-Yang
authors.initials: YY
authors.lastname: He
authors.affiliation: Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, China.
authors.forename: Yuan-Tao
authors.initials: YT
authors.lastname: Hao
authors.affiliation: Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, China.
authors.forename: Pi
authors.initials: P
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dong Feng Road East, Guangzhou, 510060, China.
authors.forename: Feng-Hua
authors.initials: FH
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dong Feng Road East, Guangzhou, 510060, China.|Beijing Hospital, Beijing, China.
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Zeng
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dong Feng Road East, Guangzhou, 510060, China. xurh@sysucc.org.cn.
authors.forename: Rui-Hua
authors.initials: RH
authors.lastname: Xu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D065637:Cytochrome P-450 CYP2A6 / Q000235:genetics; D018572:Disease-Free Survival; D004338:Drug Combinations; D005260:Female; D005472:Fluorouracil / Q000493:pharmacokinetics; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009962:Orotate Phosphoribosyltransferase / Q000097:blood; D010094:Oxonic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism*; D000071185:Pharmacogenomic Testing; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D005641:Tegafur / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism*
chemical_list: D004338:Drug Combinations; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; D009962:Orotate Phosphoribosyltransferase; D002955:Leucovorin; D005472:Fluorouracil
keywords: Advanced gastric cancer; Leucovorin; Pharmacogenetic; S-1