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

Cancer Chemother Pharmacol. 2012 Jul;70(1):25-32. doi: 10.1007/s00280-012-1883-1. Epub 2012 May 18.

Abstract

Purpose: 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.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Camptothecin / administration & dosage
  • Camptothecin / adverse effects
  • Camptothecin / analogs & derivatives
  • Capecitabine
  • Chemoradiotherapy / adverse effects
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / adverse effects
  • Deoxycytidine / analogs & derivatives
  • Diarrhea / etiology
  • Disease-Free Survival
  • Drug Administration Schedule
  • Fatigue / etiology
  • Female
  • Fluorouracil / administration & dosage
  • Fluorouracil / adverse effects
  • Fluorouracil / analogs & derivatives
  • Gene Expression Profiling*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / radiation effects
  • Humans
  • Irinotecan
  • Male
  • Middle Aged
  • Neoadjuvant Therapy
  • Neoplasm Staging
  • Rectal Neoplasms / genetics*
  • Rectal Neoplasms / pathology
  • Rectal Neoplasms / therapy*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Thymidine Phosphorylase / genetics
  • Treatment Outcome

Substances

  • Deoxycytidine
  • Capecitabine
  • Irinotecan
  • Thymidine Phosphorylase
  • Fluorouracil
  • Camptothecin