Cancer Chemotherapy and Pharmacology

, Volume 67, Issue 2, pp 339–348 | Cite as

Cetuximab and circadian chronomodulated chemotherapy as salvage treatment for metastatic colorectal cancer (mCRC): safety, efficacy and improved secondary surgical resectability

  • Francis LéviEmail author
  • Abdoulaye Karaboué
  • Lee Gorden
  • Pasquale Fabio Innominato
  • Raphael Saffroy
  • Sylvie Giacchetti
  • Dominique Hauteville
  • Catherine Guettier
  • René Adam
  • Mohamed Bouchahda
Original Article



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.


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.


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.


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.


Cetuximab Chronotherapy Liver resection Metastatic colorectal cancer Neoadjuvant chemotherapy Circadian clocks 



This work was supported in part by the Association Internationale pour la Recherche sur le Temps Biologique et la Chronothérapie (ARTBC internationale), Hôpital Paul Brousse, Villejuif, France and Merck-Serono, Lyon (France).


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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Francis Lévi
    • 1
    • 2
    • 3
    Email author
  • Abdoulaye Karaboué
    • 1
    • 2
    • 3
  • Lee Gorden
    • 3
    • 4
  • Pasquale Fabio Innominato
    • 1
    • 2
    • 3
  • Raphael Saffroy
    • 3
  • Sylvie Giacchetti
    • 1
    • 2
    • 3
  • Dominique Hauteville
    • 3
  • Catherine Guettier
    • 3
  • René Adam
    • 1
    • 2
    • 3
  • Mohamed Bouchahda
    • 1
    • 3
  1. 1.INSERM, U776 “Rythmes biologiques et cancers”, Hôpital Paul BrousseVillejuif CedexFrance
  2. 2.Univ Paris-SudOrsayFrance
  3. 3.Unité de Chronothérapie, Département de Cancérologie, Centre Hépatobiliaire, Service d’Anatomie Pathologique, and Service de Biochimie, Hôpital Paul BrousseAssistance Publique-Hôpitaux de ParisVillejuifFrance
  4. 4.Departments of Surgery and Cancer BiologyVanderbilt University Medical CenterNashvilleUSA

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