title: Cetuximab and circadian chronomodulated chemotherapy as salvage treatment for metastatic colorectal cancer (mCRC): safety, efficacy and improved secondary surgical resectability.
abstract: BACKGROUND
  Circadian rhythm disruption was linked to high serum levels of Transforming Growth Factor Receptor α, an Epidermal Growth Factor Receptor (EGFR) ligand and poor survival in patients with metastatic colorectal cancer (mCRC). We hypothesized that EGFR blockade with cetuximab would enhance the activity of chronotherapy as a result of improved circadian coordination.
  
  
  METHODS
  All the patients with mCRC referred to our unit for progression on prior chemotherapy over a 30-month-period received weekly cetuximab and fortnightly chronotherapy.
  
  
  RESULTS
  Fifty-six patients were treated with a median of six courses of fluoropyrimidine-based chemotherapy and irinotecan (61%), oxaliplatin (25%) or both (14%) after a median of three prior regimens. We found no EFGR amplification by FISH in the tumor of 27 consecutive patients. Acneiform rash and diarrhea were the most common toxicities. Objective response rate was 32.1% and positively correlated with rash grade (p = 0.025). None of the responders had K-Ras mutation in their tumor. Median progression-free and overall survival were 4.6 and 13.7 months, respectively. Complete macroscopic resections of metastases in liver, lung or other abdominopelvic sites were performed following tumor downstaging by the treatment regimen in 11 patients (21%), 8 of whom being alive at 3 years. These figures are twice as high as those reported for first-line combination of cetuximab with conventional chemotherapy or for third line chronotherapy.
  
  
  CONCLUSIONS
  The addition of cetuximab to chronotherapy allowed safe and effective therapeutic control of metastases, including their complete resection, despite previous failure of several treatment regimens.
authors.affiliation: INSERM, U776 Rythmes biologiques et cancers, Hôpital Paul Brousse, 14 avenue Paul-Vaillant-Couturier, 94807 Villejuif Cedex, France. francis.levi@inserm.fr
authors.forename: Francis
authors.initials: F
authors.lastname: Lévi
authors.forename: Abdoulaye
authors.initials: A
authors.lastname: Karaboué
authors.forename: Lee
authors.initials: L
authors.lastname: Gorden
authors.forename: Pasquale Fabio
authors.initials: PF
authors.lastname: Innominato
authors.forename: Raphael
authors.initials: R
authors.lastname: Saffroy
authors.forename: Sylvie
authors.initials: S
authors.lastname: Giacchetti
authors.forename: Dominique
authors.initials: D
authors.lastname: Hauteville
authors.forename: Catherine
authors.initials: C
authors.lastname: Guettier
authors.forename: René
authors.initials: R
authors.lastname: Adam
authors.forename: Mohamed
authors.initials: M
authors.lastname: Bouchahda
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000601:surgery; D018572:Disease-Free Survival; D055870:Drug Chronotherapy; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005784:Gene Amplification / Q000235:genetics; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000628:therapy; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D011379:Prognosis; D016879:Salvage Therapy / Q000009:adverse effects / Q000379:methods*; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000077146:Irinotecan; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin