title: Phase II and gene expression analysis trial of neoadjuvant capecitabine plus irinotecan followed by capecitabine-based chemoradiotherapy for locally advanced rectal cancer: Hoosier Oncology Group GI03-53.
abstract: OBJECTIVE
  We designed this study in locally advanced rectal cancer to determine the pathological response, toxicity, and disease-free survival (DFS) with induction capecitabine plus irinotecan followed by capecitabine-based chemoradiotherapy (CRT) and analyze the gene expression of enzymes involved in the metabolism of capecitabine and irinotecan for associations with response and toxicity.
  
  
  METHODS
  Patients with T3/T4 or node positive rectal cancer were treated with capecitabine 1,000 mg/m(2) twice daily (BID) days 1-14, and irinotecan 200 mg/m(2) on day 1 every 21 days for 2 cycles, followed by capecitabine 825 mg/m(2) BID days 1-5 per week with concurrent radiotherapy 50.4 Gy in 28 fractions. Surgical resection occurred a median of 7.4 weeks after CRT. Gene expression levels or sequencing were used to analyze carboxylesterase-converting enzymes (CES1, CES2), thymidylate synthase (TS), thymidine phosphorylase (TP), dehydropyrimidine dehydrogenase (DPD), topoisomerase I (TOPO I), and uridine-diphosphate (UDP) glucuronosyl transferase 1A1 in pre- and post-treatment tumor and normal tissue samples.
  
  
  RESULTS
  Twenty-two patients were enrolled, and 18 completed neoadjuvant therapy and underwent R0 resection. Two patients with UGT1A1 7/7 had grade 3 and 4 neutropenic fever and sepsis. Pathological complete response (pCR) occurred in 6 of 18 patients (33 %) and 10 (56 %) had tumor and/or nodal downstaging. The 3-year DFS was 75.5 % (95 % CI, 39.7-91.8 %). Locoregional control rate was 100 %. We observed higher TP gene expression in pCR patients, but no correlations with toxicity.
  
  
  CONCLUSIONS
  This neoadjuvant regimen was safe and demonstrated significant antitumor activity. High TP tumor gene expression was associated with obtaining pCR.
authors.affiliation: Indiana University Melvin and Bren Simon Cancer Center, 535 Barnhill Drive, RT 473, Indianapolis, IN 46202, USA. gchiorea@iupui.edu
authors.forename: E Gabriela
authors.initials: EG
authors.lastname: Chiorean
authors.forename: Sonal
authors.initials: S
authors.lastname: Sanghani
authors.forename: Marissa A
authors.initials: MA
authors.lastname: Schiel
authors.forename: Menggang
authors.initials: M
authors.lastname: Yu
authors.forename: Matthew
authors.initials: M
authors.lastname: Burns
authors.forename: Yan
authors.initials: Y
authors.lastname: Tong
authors.forename: David T
authors.initials: DT
authors.lastname: Hinkle
authors.forename: Nicki
authors.initials: N
authors.lastname: Coleman
authors.forename: Bruce
authors.initials: B
authors.lastname: Robb
authors.forename: Julia
authors.initials: J
authors.lastname: LeBlanc
authors.forename: Romnee
authors.initials: R
authors.lastname: Clark
authors.forename: Jose
authors.initials: J
authors.lastname: Bufill
authors.forename: Colleen
authors.initials: C
authors.lastname: Curie
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Loehrer
authors.forename: Higinia
authors.initials: H
authors.lastname: Cardenes
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D000069287:Capecitabine; D059248:Chemoradiotherapy / Q000009:adverse effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D003967:Diarrhea / Q000209:etiology; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005221:Fatigue / Q000209:etiology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D012004:Rectal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013939:Thymidine Phosphorylase / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D003841:Deoxycytidine; D000069287:Capecitabine; D000077146:Irinotecan; D013939:Thymidine Phosphorylase; D005472:Fluorouracil; D002166:Camptothecin