title: Conversion to resection of liver metastases from colorectal cancer with hepatic artery infusion of combined chemotherapy and systemic cetuximab in multicenter trial OPTILIV.
abstract: BACKGROUND
  Systemic chemotherapy typically converts previously unresectable liver metastases (LM) from colorectal cancer to curative intent resection in ∼15% of patients. This European multicenter phase II trial tested whether hepatic artery infusion (HAI) with triplet chemotherapy and systemic cetuximab could increase this rate to 30% in previously treated patients.
  
  
  METHODS
  Participants had unresectable LM from wt KRAS colorectal cancer. Main non-inclusion criteria were advanced extra hepatic disease, prior HAI and grade 3 neuropathy. Irinotecan (180 mg/m(2)), oxaliplatin (85 mg/m(2)) and 5-fluorouracil (2800 mg/m(2)) were delivered via an implanted HAI access port and combined with i.v. cetuximab (500 mg/m(2)) every 14 days. Multidisciplinary decisions to resect LM were taken after every three courses. The rate of macroscopic complete resections (R0 + R1) of LM, progression-free survival (PFS) and overall survival (OS) were computed according to intent to treat.
  
  
  RESULTS
  The patient population consisted of 42 men and 22 women, aged 33-76 years, with a median of 10 LM involving a median of six segments. Up to 3 extrahepatic lesions of <1 cm were found in 41% of the patients. A median of six courses was delivered. The primary end point was met, with R0-R1 hepatectomy for 19 of the 64 previously treated patients, 29.7% (95% confidence interval 18.5-40.9). Grade 3-4 neutropenia (42.6%), abdominal pain (26.2%), fatigue (18%) and diarrhea (16.4%) were frequent. Objective response rate was 40.6% (28.6-52.3). Median PFS and OS reached 9.3 (7.8-10.9) and 25.5 months (18.8-32.1) respectively. Those with R0-R1 hepatectomy had a median OS of 35.2 months (32.6-37.8), with 37.4% (23.6-51.2) alive at 4 years.
  
  
  CONCLUSIONS
  The coordination of liver-specific intensive chemotherapy and surgery had a high curative intent potential that deserves upfront randomized testing.
  EUDRACT 2007-004632-24, NCT00852228.
authors.affiliation: UMRS 776 'Biological Rhythms and Cancers', INSERM, Villejuif Université Paris Sud 11, Orsay Assistance Publique-Hopitaux de Paris, Department of Medical Oncology, Department of Hepatobiliary Center and Radiology, Paul Brousse Hospital, Villejuif, France Cancer Chronotherapy Unit, Warwick Medical School, Coventry, UK f.levi@warwick.ac.uk.
authors.forename: F A
authors.initials: FA
authors.lastname: Lévi
authors.affiliation: Service d'Oncologie Digestive, Institut Gustave Roussy, Villejuif.
authors.forename: V
authors.initials: V
authors.lastname: Boige
authors.affiliation: Department of Medical Oncology, Hôpital Huriez, Lille.
authors.forename: M
authors.initials: M
authors.lastname: Hebbar
authors.affiliation: Hôpital Saint-André, Department of Medical Oncology, Centre Hospitalo-Universitaire, Bordeaux.
authors.forename: D
authors.initials: D
authors.lastname: Smith
authors.affiliation: Service d'Hépato-Gastro-Entérologie, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Lepère
authors.affiliation: Department of Oncology, Centre Hospitalier Chrétien, Clinique Saint-Joseph, Liège, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Focan
authors.affiliation: UMRS 776 'Biological Rhythms and Cancers', INSERM, Villejuif Université Paris Sud 11, Orsay Assistance Publique-Hopitaux de Paris, Department of Medical Oncology, Department of Hepatobiliary Center and Radiology, Paul Brousse Hospital, Villejuif, France.
authors.forename: A
authors.initials: A
authors.lastname: Karaboué
authors.affiliation: Department of Oncology, University Hospital of Purpan, Toulouse, France.
authors.forename: R
authors.initials: R
authors.lastname: Guimbaud
authors.affiliation: Medical Oncology Unit, Hospital Fernando Foncesca, Amadora, Portugal.
authors.forename: C
authors.initials: C
authors.lastname: Carvalho
authors.affiliation: Department of Oncology, Santa Maria Degli Angeli General Hospital, Pordenone, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Tumolo
authors.affiliation: UMRS 776 'Biological Rhythms and Cancers', INSERM, Villejuif Université Paris Sud 11, Orsay Assistance Publique-Hopitaux de Paris, Department of Medical Oncology, Department of Hepatobiliary Center and Radiology, Paul Brousse Hospital, Villejuif, France Cancer Chronotherapy Unit, Warwick Medical School, Coventry, UK.
authors.forename: P
authors.initials: P
authors.lastname: Innominato
authors.affiliation: Assistance Publique-Hopitaux de Paris, Department of Medical Oncology, Department of Hepatobiliary Center and Radiology, Paul Brousse Hospital, Villejuif, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Ajavon
authors.affiliation: Department of Medical Oncology, Hôpital Huriez, Lille.
authors.forename: S
authors.initials: S
authors.lastname: Truant
authors.affiliation: Université Paris Sud 11, Orsay Assistance Publique-Hopitaux de Paris, Department of Medical Oncology, Department of Hepatobiliary Center and Radiology, Paul Brousse Hospital, Villejuif, France.
authors.forename: D
authors.initials: D
authors.lastname: Castaing
authors.affiliation: Service d'Oncologie Digestive, Institut Gustave Roussy, Villejuif.
authors.forename: T
authors.initials: T
authors.lastname: De Baere
authors.affiliation: Assistance Publique-Hopitaux de Paris, Department of Medical Oncology, Department of Hepatobiliary Center and Radiology, Paul Brousse Hospital, Villejuif, France.
authors.forename: F
authors.initials: F
authors.lastname: Kunstlinger
authors.affiliation: UMRS 776 'Biological Rhythms and Cancers', INSERM, Villejuif Université Paris Sud 11, Orsay Assistance Publique-Hopitaux de Paris, Department of Medical Oncology, Department of Hepatobiliary Center and Radiology, Paul Brousse Hospital, Villejuif, France.
authors.forename: M
authors.initials: M
authors.lastname: Bouchahda
authors.affiliation: Cancer Chronotherapy Unit, Warwick Medical School, Coventry, UK.
authors.forename: M
authors.initials: M
authors.lastname: Afshar
authors.affiliation: Service d'Hépato-Gastro-Entérologie, Hôpital Européen Georges Pompidou, Paris, France Université René Descartes, Paris V, France.
authors.forename: P
authors.initials: P
authors.lastname: Rougier
authors.affiliation: UMRS 776 'Biological Rhythms and Cancers', INSERM, Villejuif Université Paris Sud 11, Orsay Assistance Publique-Hopitaux de Paris, Department of Medical Oncology, Department of Hepatobiliary Center and Radiology, Paul Brousse Hospital, Villejuif, France.
authors.forename: R
authors.initials: R
authors.lastname: Adam
authors.affiliation: Université Paris Sud 11, Orsay Assistance Publique-Hopitaux de Paris, Department of Medical Oncology, Department of Hepatobiliary Center and Radiology, Paul Brousse Hospital, Villejuif, France Service d'Oncologie Digestive, Institut Gustave Roussy, Villejuif.
authors.forename: M
authors.initials: M
authors.lastname: Ducreux
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use; D000068818:Cetuximab / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D006498:Hepatectomy; D006499:Hepatic Artery; D006801:Humans; D007261:Infusions, Intra-Arterial; D000077146:Irinotecan; D008099:Liver / Q000473:pathology / Q000601:surgery*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary / Q000601:surgery*; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D000077150:Oxaliplatin; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D016896:Treatment Outcome
chemical_list: C117307:KRAS protein, human; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000077146:Irinotecan; D016283:Proto-Oncogene Proteins p21(ras); D000068818:Cetuximab; D005472:Fluorouracil; D002166:Camptothecin
keywords: cetuximab; chronotherapy; colorectal cancer; hepatectomy; hepatic artery infusion; liver metastases