Cetuximab and circadian chronomodulated chemotherapy as salvage treatment for metastatic colorectal cancer (mCRC): safety, efficacy and improved secondary surgical resectability.
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.
Lévi
Francis
F
INSERM, U776 Rythmes biologiques et cancers, Hôpital Paul Brousse, 14 avenue Paul-Vaillant-Couturier, 94807 Villejuif Cedex, France. francis.levi@inserm.fr
Karaboué
Abdoulaye
A
Gorden
Lee
L
Innominato
Pasquale Fabio
PF
Saffroy
Raphael
R
Giacchetti
Sylvie
S
Hauteville
Dominique
D
Guettier
Catherine
C
Adam
René
R
Bouchahda
Mohamed
M
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
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