title: High Resectability Rate of Initially Unresectable Colorectal Liver Metastases After UGT1A1-Adapted High-Dose Irinotecan Combined with LV5FU2 and Cetuximab: A Multicenter Phase II Study (ERBIFORT).
abstract: The purpose of this study was to assess the efficacy and tolerance of induction chemotherapy combining LV5FU2 with increased doses of irinotecan adapted to UGT1A1 genotyping and cetuximab in untreated potentially resectable liver metastases of colorectal cancer.
  
  
  
  Twenty-six patients, PS 0-1, with class II hepatic metastases received chemotherapy combining irinotecan 260 mg/m(2) on day 1 for UGT1A1 6/6 and 6/7 genotypes and 220 mg/m(2) for UGT1A1 7/7 genotypes, with leucovorin on day 1, 5FU 400 mg/m(2) bolus on day 1 and continuous 5FU infusion for 46 h, and cetuximab on day 1 (day 1 = day 14). Primary prevention with lenograstim (day 5-9) was given to UGT1A1 6/7 and 7/7 genotypes. The primary endpoint was the response rate (RECIST1.1), and the secondary endpoints were tolerance (NCI-CTC criteria) and R0 resection rate.
  
  
  
  The average number of cycles per patient was 6 (±1.9). The UGT1A1 genotype was 6/6 in 34.6 %, 6/7 in 53.9 %, and 7/7 in 11.5 % of patients. At 6 cycles, 18 patients (69.2 %) presented a partial response, 5 patients (19.2 %) had stable disease, 2 patients (7.7 %) died independently of chemotherapy, and 1 patient (3.9 %) refused the treatment after 3 cycles. Four patients received 2 more cycles and the cumulative response rate at 8 cycles was 76.9 % (20/26). There was no progression. Among assessable patients (n = 23), the overall response rate was 82.6 % and 21 patients (80.7 %) had a metastasis resection. The most frequent grade 3-4 toxicities were neutropenia (31 %), diarrhea (20.8 %), and anorexia (16.4 %). There were no deaths due to toxicity.
  
  
  
  High-dose FOLFIRI combined with cetuximab yielded high response rates and enabled complete resection of class II hepatic metastases in most patients. It seemed to be well-tolerated among healthy selected patients thanks to irinotecan dose adaptation according to UGT1A1 pharmacogenomics status. This intensified chemotherapy regimen needs to be confirmed in a randomized, phase III study.
authors.affiliation: Department of Gastroenterology and Digestive Oncology, LINA EA4624 Jean Monet University, University Hospital of Saint Etienne, 42055, Saint Etienne Cedex 2, France. j.marc.phelip@chu-st-etienne.fr.
authors.forename: Jean Marc
authors.initials: JM
authors.lastname: Phelip
authors.affiliation: Sainte Catherine Institute, Avignon, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Mineur
authors.affiliation: Leon Berard Center, Lyon, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: De la Fouchardière
authors.affiliation: Claudius Regaud Institute, Toulouse, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Chatelut
authors.affiliation: University Hospital of Grenoble, Grenoble, France.
authors.forename: Jean Louis
authors.initials: JL
authors.lastname: Quesada
authors.affiliation: Department of Gastroenterology and Digestive Oncology, LINA EA4624 Jean Monet University, University Hospital of Saint Etienne, 42055, Saint Etienne Cedex 2, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Roblin
authors.affiliation: University Hospital of Clermont Ferrand, Clermont Ferrand, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Pezet
authors.affiliation: University Hospital of Grenoble, Grenoble, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Mendoza
authors.affiliation: University Hospital of Clermont Ferrand, Clermont Ferrand, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Buc
authors.affiliation: Leon Berard Center, Lyon, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Rivoire
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D000068818:Cetuximab / Q000008:administration & dosage; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology / Q000601:surgery*; D003131:Combined Modality Therapy; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005500:Follow-Up Studies; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000556:secondary / Q000601:surgery*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D015996:Survival Rate; D000099148:UGT1A1 Enzyme
chemical_list: D002166:Camptothecin; D000068818:Cetuximab; D005472:Fluorouracil; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D002955:Leucovorin; D000099148:UGT1A1 Enzyme