title: Early tumour response as a survival predictor in previously- treated patients receiving triplet hepatic artery infusion and intravenous cetuximab for unresectable liver metastases from wild-type KRAS colorectal cancer.
abstract: Early tumour shrinkage has been associated with improved survival in patients receiving cetuximab-based systemic chemotherapy for liver metastases from colorectal cancer (LM-CRC). We tested this hypothesis for previously treated LM-CRC patients receiving cetuximab (500 mg/m2) and triplet hepatic artery infusion (HAI) within European trial OPTILIV.
  
  
  
  Irinotecan (180 mg/m2), 5-fluorouracil (2800 mg/m2) and oxaliplatin (85 mg/m2) were given as chronomodulated or conventional delivery. Patients were retrospectively categorised as early responders (complete or partial RECIST response after three courses) or non-early responders (late or no response). Prognostic factors were determined using multivariate logistic or Cox regression models.
  
  
  
  Response was assessed in 57 of 64 registered patients (89%), who had previously received one to three prior systemic chemotherapy protocols. An early response occurred at 6 weeks in 16 patients (28%; 9 men, 7 women), aged 33-76 years, with a median of 12 liver metastases (LMs) (2-50), involving five segments (1-8). Ten patients had a late response, and 31 patients had no response. Grade 3-4 fatigue selectively occurred in the non-early responders (0% versus 26%; p = 0.024). Early tumour response was jointly predicted by chronomodulation-odds ratio (OR): 6.0 (1.2-29.8; p = 0.029)-and LM diameter ≤57 mm-OR: 5.3 (1.1-25.0; p = 0.033). Early tumour response predicted for both R0-R1 liver resection-OR: 11.8 (1.4-100.2; p = 0.024) and overall survival-hazard ratio: 0.39 (0.17-0.88; p = 0.023) in multivariate analyses.
  
  
  
  Early tumour response on triplet HAI and systemic cetuximab predicted for complete macroscopic liver resection and prolonged survival for LM-CRC patients within a multicenter conversion-to-resection medicosurgical strategy. Confirmation is warranted for early response on HAI to guide decision making. Protocol numbers: EUDRACT 2007-004632-24 NCT00852228.
authors: AP-HP, Departments of Medical Oncology, Hepato-Biliary Surgery and Radiology, Paul Brousse Hospital, Villejuif, France; INSERM and Paris-Saclay UMR S935, CNRS Campus, Villejuif, France; Ramsay-GDS Mousseau Clinics, Evry, France.
authors: Mohamed
authors: M
authors: Bouchahda
authors: Gustave-Roussy Institut, Villejuif, France.
authors: Valérie
authors: V
authors: Boige
authors: Saint André Hospital, Bordeaux, France.
authors: Denis
authors: D
authors: Smith
authors: INSERM and Paris-Saclay UMR S935, CNRS Campus, Villejuif, France; AK-SCIENCES, Research and Therapeutic Innovation, Vitry-Sur-Seine, France.
authors: Abdoulaye
authors: A
authors: Karaboué
authors: Gustave-Roussy Institut, Villejuif, France.
authors: Michel
authors: M
authors: Ducreux
authors: Medical Oncology Unit, Huriez Hospital, Lille, France.
authors: Mohamed
authors: M
authors: Hebbar
authors: Georges Pompidou European Hospital, Paris, France.
authors: Céline
authors: C
authors: Lepère
authors: CHC Saint Joseph Clinics, Liège, Belgium.
authors: Christian
authors: C
authors: Focan
authors: Digestive Medical Oncology Unit, Toulouse University Hospital, Toulouse, France.
authors: Rosine
authors: R
authors: Guimbaud
authors: AP-HP, Departments of Medical Oncology, Hepato-Biliary Surgery and Radiology, Paul Brousse Hospital, Villejuif, France; INSERM and Paris-Saclay UMR S935, CNRS Campus, Villejuif, France; Cancer Chronotherapy Unit, Warwick Medical School, Coventry, United Kingdom.
authors: Pasquale
authors: P
authors: Innominato
authors: AP-HP, Departments of Medical Oncology, Hepato-Biliary Surgery and Radiology, Paul Brousse Hospital, Villejuif, France.
authors: Sameh
authors: S
authors: Awad
authors: Medical Oncology Unit, Fernando Fonseca Hospital, Amadora, Portugal.
authors: Carlos
authors: C
authors: Carvalho
authors: Santa Maria Degli Angeli General Hospital, Pordenone, Italy.
authors: Salvatore
authors: S
authors: Tumolo
authors: Medical Oncology Unit, Huriez Hospital, Lille, France.
authors: Stephanie
authors: S
authors: Truant
authors: Gustave-Roussy Institut, Villejuif, France.
authors: Thierry
authors: T
authors: De Baere
authors: AP-HP, Departments of Medical Oncology, Hepato-Biliary Surgery and Radiology, Paul Brousse Hospital, Villejuif, France.
authors: Denis
authors: D
authors: Castaing
authors: Georges Pompidou European Hospital, Paris, France.
authors: Philippe
authors: P
authors: Rougier
authors: AP-HP, Departments of Medical Oncology, Hepato-Biliary Surgery and Radiology, Paul Brousse Hospital, Villejuif, France.
authors: Jean-François
authors: JF
authors: Morère
authors: Georges Pompidou European Hospital, Paris, France.
authors: Julien
authors: J
authors: Taieb
authors: AP-HP, Departments of Medical Oncology, Hepato-Biliary Surgery and Radiology, Paul Brousse Hospital, Villejuif, France; INSERM and Paris-Saclay UMR S935, CNRS Campus, Villejuif, France.
authors: René
authors: R
authors: Adam
authors: AP-HP, Departments of Medical Oncology, Hepato-Biliary Surgery and Radiology, Paul Brousse Hospital, Villejuif, France; INSERM and Paris-Saclay UMR S935, CNRS Campus, Villejuif, France; Cancer Chronotherapy Unit, Warwick Medical School, Coventry, United Kingdom. Electronic address: F.Levi@warwick.ac.uk.
authors: Francis
authors: F
authors: Lévi
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000556:secondary; 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* / Q000473:pathology; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006499:Hepatic Artery; D006801:Humans; D007261:Infusions, Intra-Arterial; D007262:Infusions, Intravenous; D000077146:Irinotecan; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000556:secondary; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D015996:Survival Rate; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000077146:Irinotecan; D000068818:Cetuximab; D005472:Fluorouracil; D002166:Camptothecin
keywords: Colorectal cancer; Early tumour response; Hepatic artery infusion; Liver metastases; Triplet chemotherapy