title: A phase II study of preoperative chemoradiation with tegafur-uracil plus leucovorin for locally advanced rectal cancer with pharmacogenetic analysis.
abstract: BACKGROUND
  This study aimed to evaluate the efficacy of a high dose of oral tegafur-uracil (400 mg/m2) plus leucovorin with preoperative chemoradiation of locally advanced rectal cancer and to explore the impact of polymorphisms of cytochrome P 2A6 (CYP2A6), uridine monophosphate synthetase (UMPS), and ATP-binding cassette B1 (ABCB1) on clinical outcome.
  
  
  METHODS
  Patients with cT3 or cT4 rectal cancer were enrolled and were given tegafur-uracil 400 mg/m2/day and leucovorin 90 mg/m2/day for 7 days a week during preoperative chemoradiation (50.4 Gy/28 fractions) in this phase II trial. Primary endpoint was pathologic complete response rate, and the secondary endpoint was to explore the association between clinical outcomes and genetic polymorphisms CYP2A6 (*4, *7, *9 and *10), UMPS G638C, and three ABCB1 genotypes (C1236T, C3435T, and G2677T).
  
  
  RESULTS
  Ninety-one patients were given study treatment, and 90 underwent surgery. Pathologic complete response was noted in 10 patients (11.1%). There was no grade 4 or 5 toxicity; 20 (22.0%) experienced grade 3 toxicities, including diarrhea (10, 11.0%), abdominal pain (2, 2.2%), and anemia (2, 2.2%). Relapse-free survival and overall survival at 5 years were 88.6% and 94.2%, respectively. Patients with the UMPS 638 CC genotype experienced significantly more frequent grade 2 or 3 diarrhea (p for trend = 0.018).
  
  
  CONCLUSIONS
  Preoperative chemoradiation with tegafur-uracil 400 mg/m2/day with leucovorin was feasible, but did not meet the expected pathologic complete response rate. The UMPS 638 CC genotype might be a candidate biomarker predicting toxicity in patients receiving tegafur-uracil/leucovorin-based preoperative chemoradiation for locally advanced rectal cancer.
  
  
  BACKGROUND
  ISRCTN11812525 , registered on 25 July 2016. Retrospectively registered.
authors.affiliation: Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Ilsan-ro 323, Goyang-si, Gyeonggi-do, 10408, Republic of Korea.|Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea.
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Ilsan-ro 323, Goyang-si, Gyeonggi-do, 10408, Republic of Korea.
authors.forename: Ji Yeon
authors.initials: JY
authors.lastname: Baek
authors.affiliation: Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Ilsan-ro 323, Goyang-si, Gyeonggi-do, 10408, Republic of Korea.
authors.forename: Jae Hwan
authors.initials: JH
authors.lastname: Oh
authors.affiliation: Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Ilsan-ro 323, Goyang-si, Gyeonggi-do, 10408, Republic of Korea.
authors.forename: Sung Chan
authors.initials: SC
authors.lastname: Park
authors.affiliation: Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Ilsan-ro 323, Goyang-si, Gyeonggi-do, 10408, Republic of Korea.
authors.forename: Dae Kyung
authors.initials: DK
authors.lastname: Sohn
authors.affiliation: Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Ilsan-ro 323, Goyang-si, Gyeonggi-do, 10408, Republic of Korea.
authors.forename: Min Ju
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Ilsan-ro 323, Goyang-si, Gyeonggi-do, 10408, Republic of Korea.
authors.forename: Hee Jin
authors.initials: HJ
authors.lastname: Chang
authors.affiliation: Department of Laboratory Medicine, Research Institute and Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 10408, Republic of Korea. ksy@ncc.re.kr.
authors.forename: Sun-Young
authors.initials: SY
authors.lastname: Kong
authors.affiliation: Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Ilsan-ro 323, Goyang-si, Gyeonggi-do, 10408, Republic of Korea.
authors.forename: Dae Yong
authors.initials: DY
authors.lastname: Kim
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects; D059186:Chemoradiotherapy, Adjuvant / Q000009:adverse effects / Q000379:methods*; D065637:Cytochrome P-450 CYP2A6 / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000235:genetics; D020360:Neoadjuvant Therapy / Q000009:adverse effects / Q000379:methods*; D009962:Orotate Phosphoribosyltransferase / Q000235:genetics; D009964:Orotidine-5'-Phosphate Decarboxylase / Q000235:genetics; D000071185:Pharmacogenomic Testing; D020641:Polymorphism, Single Nucleotide; D012004:Rectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000532:radiotherapy; D005641:Tegafur / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome; D014498:Uracil / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D009097:Multienzyme Complexes; D005641:Tegafur; D014498:Uracil; C027157:uridine 5'-monophosphate synthase; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; D009962:Orotate Phosphoribosyltransferase; D009964:Orotidine-5'-Phosphate Decarboxylase; D002955:Leucovorin
keywords: Chemoradiotherapy; Rectal neoplasms; Tegafur; Uridine monophosphate synthetase