title: Circulating Tumor Cell Enumeration in a Phase II Trial of a Four-Drug Regimen in Advanced Colorectal Cancer.
abstract: BACKGROUND
  Multidrug regimens are active against advanced colorectal cancer (ACRC). However, the increased toxicity requires the use of biomarkers to select the patients who will derive the most benefit. We assessed circulating tumor cells (CTCs) as a prognostic biomarker in patients treated with a 4-drug regimen.
  
  
  METHODS
  A single-arm phase II trial (Erbitux Study of CPT11, Oxaliplatin, UFToral Targeted-therapy [eSCOUT]) was undertaken in patients with previously untreated KRAS wild-type ACRC using a regimen of irinotecan, oxaliplatin, and tegafur-uracil with leucovorin and cetuximab. Baseline CTCs were enumerated using CellSearch. The endpoints were an objective response rate (ORR) and overall survival (OS). We modeled our results and compared them with those modeled for the capecitabine, oxaliplatin, bevacizumab +/- cetuximab (CAIRO2) trial, stratifying patients a priori into low (< 3) and high (≥ 3) CTC groups.
  
  
  RESULTS
  For 48 eligible patients, the best ORR from the 4-drug regimen was 71%, with a disease control rate of 98%. The median OS for patients with a high and low CTC count was 18.7 and 22.3 months (log-rank test, P = .038), respectively. In our modeled data, for patients with a low CTC count, no differences were found between the median OS in the eSCOUT trial and that in the CAIRO2 trial (22.2 vs. 22.0 months). However, for the high CTC group, a clinically relevant improvement was seen in median OS (eSCOUT vs. CAIRO2, 18.7 vs. 13.7 months; P = .001).
  
  
  CONCLUSIONS
  These data are hypothesis generating-for patients with ACRC, stratification by CTC count can identify those who might benefit the most from an intensive 4-drug regimen, avoiding high-toxicity regimens in low CTC groups. This hypothesis warrants validation in a phase III biomarker-driven trial.
authors: Clinical and Experimental Pharmacology, Cancer Research UK Manchester Institute, Manchester, UK; The Christie NHS Foundation Trust, Manchester, UK; Institute of Cancer Sciences, University of Manchester, Manchester, UK.
authors: Matthew G
authors: MG
authors: Krebs
authors: Clinical and Experimental Pharmacology, Cancer Research UK Manchester Institute, Manchester, UK; Institute of Cancer Sciences, University of Manchester, Manchester, UK.
authors: Andrew G
authors: AG
authors: Renehan
authors: Clinical and Experimental Pharmacology, Cancer Research UK Manchester Institute, Manchester, UK.
authors: Alison
authors: A
authors: Backen
authors: North Wales Cancer Treatment Centre, Wales, UK.
authors: Simon
authors: S
authors: Gollins
authors: The Royal Marsden Hospital, London, UK.
authors: Ian
authors: I
authors: Chau
authors: The Christie NHS Foundation Trust, Manchester, UK.
authors: Jurjees
authors: J
authors: Hasan
authors: The Christie NHS Foundation Trust, Manchester, UK; Institute of Cancer Sciences, University of Manchester, Manchester, UK.
authors: Juan W
authors: JW
authors: Valle
authors: Clinical and Experimental Pharmacology, Cancer Research UK Manchester Institute, Manchester, UK.
authors: Karen
authors: K
authors: Morris
authors: The Christie NHS Foundation Trust, Manchester, UK.
authors: Janette
authors: J
authors: Beech
authors: The Christie NHS Foundation Trust, Manchester, UK.
authors: Linda
authors: L
authors: Ashcroft
authors: The Christie NHS Foundation Trust, Manchester, UK. Electronic address: mark.saunders@christie.nhs.uk.
authors: Mark P
authors: MP
authors: Saunders
authors: Clinical and Experimental Pharmacology, Cancer Research UK Manchester Institute, Manchester, UK.
authors: Caroline
authors: C
authors: Dive
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D000069287:Capecitabine / Q000008:administration & dosage; D000068818:Cetuximab / Q000008:administration & dosage; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005500:Follow-Up Studies; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009360:Neoplastic Cells, Circulating / Q000473:pathology*; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D011379:Prognosis; D011446:Prospective Studies; D015996:Survival Rate
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000068258:Bevacizumab; D000069287:Capecitabine; D000077146:Irinotecan; D000068818:Cetuximab; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin
keywords: Biomarker; CellSearch; Cetuximab; Circulating tumor cells; Colorectal cancer