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

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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.

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References

  1. Giacchetti S, Itzhaki M, Gruia G et al (1999) Long-term survival of patients with unresectable colorectal cancer liver metastases following infusional chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and surgery. Ann Oncol 10:663–669

    Article  CAS  PubMed  Google Scholar 

  2. Adam R, Delvart V, Pascal G et al (2004) Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg 240:644–657

    Article  PubMed  Google Scholar 

  3. Folprecht G, Grothey A, Alberts S et al (2005) Neoadjuvant treatment of unresectable colorectal liver metastases: correlation between tumour response and resection rates. Ann Oncol 16:1311–1319

    Article  CAS  PubMed  Google Scholar 

  4. Adam R, Aloia T, Lévi F et al (2007) Hepatic resection after rescue cetuximab treatment for colorectal liver metastases previously refractory to conventional systemic therapy. J Clin Oncol 25:4593–4602

    Article  CAS  PubMed  Google Scholar 

  5. Jonker DJ, O’Callaghan CJ, Karapetis CS et al (2007) Cetuximab for the treatment of colorectal cancer. N Engl J Med 357:2040–2048

    Article  CAS  PubMed  Google Scholar 

  6. Sobrero AF, Maurel J, Fehrenbacher L et al (2008) EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol 26:2311–2319

    Article  CAS  PubMed  Google Scholar 

  7. Pessino A, Artale S, Sciallero S et al (2008) First-line single-agent cetuximab in patients with advanced colorectal cancer. Ann Oncol 19(4):711–716

    Article  CAS  PubMed  Google Scholar 

  8. Van Cutsem E, Köhne CH, Hitre E et al (2009) Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360:1408–1417

    Article  PubMed  Google Scholar 

  9. Cunningham D, Humblet Y, Siena S et al (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:391–392

    Article  Google Scholar 

  10. Lenz HJ, Van Cutsem EV, Khambata-Ford S et al (2006) Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clin Oncol 24:4914–4921

    Article  CAS  PubMed  Google Scholar 

  11. Shim KS, Kim KH, Park BW et al (1998) Increased serum levels of transforming growth factor-alpha in patients with colorectal cancer. Dis Colon Rectum 41(2):219–224

    Article  CAS  PubMed  Google Scholar 

  12. Rich T, Innominato PF, Boerner J et al (2005) Elevated serum cytokines correlated with altered behavior, serum cortisol rhythm, and dampened 24-hour rest-activity patterns in patients with metastatic colorectal cancer. Clin Cancer Res 11:1757–1764

    Article  CAS  PubMed  Google Scholar 

  13. Kramer A, Yang FC, Snodgrass P et al (2001) Regulation of daily locomotor activity and sleep by hypothalamic EGF receptor signaling. Science 294:2511–2515

    Article  CAS  PubMed  Google Scholar 

  14. Snodgrass-Belt P, Gilbert JL, Davis FC (2005) Central administration of transforming growth factor-alpha and neuregulin-1 suppress active behaviors and cause weight loss in hamsters. Brain Res 1038:171–182

    Article  CAS  PubMed  Google Scholar 

  15. Lévi F, Schibler U (2007) Circadian rhythms: mechanisms and therapeutic implications. Annu Rev Pharmacol Toxicol 47:593–628

    Article  PubMed  Google Scholar 

  16. Reddy AB, Karp NA, Maywood ES et al (2006) Circadian orchestration of the hepatic proteome. Curr Biol 16:1107–1115

    Article  CAS  PubMed  Google Scholar 

  17. Iurisci I, Filipski E, Reinhardt J et al (2006) Improved tumor control through circadian clock induction by Seliciclib, a cyclin-dependent kinase inhibitor. Cancer Res 66:10720–10728

    Article  CAS  PubMed  Google Scholar 

  18. Levi FA, Zidani R, Vannetzel JM et al (1994) Chronomodulated versus fixed-infusion-rate delivery of ambulatory chemotherapy with oxaliplatin, fluorouracil, and folinic acid (leucovorin) in patients with colorectal cancer metastases: a randomized multi-institutional trial. J Natl Cancer Inst 86:1608–1617

    Article  CAS  PubMed  Google Scholar 

  19. Levi F, Zidani R, Misset JL (1997) Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. International Organization for Cancer Chronotherapy. Lancet 350:681–686

    Article  CAS  PubMed  Google Scholar 

  20. Giacchetti S, Bjarnason G, Garufi C et al (2006) Phase III trial comparing 4-day chronomodulated therapy versus 2-day conventional delivery of fluorouracil, leucovorin, and oxaliplatin as first-line chemotherapy of metastatic colorectal cancer: the European Organisation for Research and Treatment of Cancer Chronotherapy Group. J Clin Oncol 24:3562–3569

    Article  CAS  PubMed  Google Scholar 

  21. Lévi F, Focan C, Karaboué A et al (2007) Implications of circadian clocks for the rhythmic delivery of cancer therapeutics. Adv Drug Deliv Rev 59:1015–1035

    Article  PubMed  Google Scholar 

  22. Folprecht G, Gruenberger T, Bechstein WO et al (2010) Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial. Lancet Oncol 11(1):38–47

    Google Scholar 

  23. Perez-Soler R, Saltz L (2005) Cutaneous adverse effects with HER1/EGFR-targeted agents: is there a silver lining? J Clin Oncol 23:5235–5246

    Article  PubMed  Google Scholar 

  24. Tejpar S, Peeters M, Humblet Y et al (2007) Phase I/II study of cetuximab dose-escalation in patients with metastatic colorectal cancer (mCRC) with no or slight skin reactions on cetuximab standard dose treatment (EVEREST): pharmacokinetic (PK), pharmacodynamic (PD) and efficacy data. J Clin Oncol 25(Suppl 18S):172s (Abstr 4037)

  25. Vincenzi B, Santini D, Rabitti C et al (2006) Cetuximab and irinotecan as third-line therapy in advanced colorectal cancer patients: a single centre phase II trial. Br J Cancer 94:792–797

    Article  CAS  PubMed  Google Scholar 

  26. Souglakos J, Kalykaki A, Vamvakas L et al (2007) Phase II trial of capecitabine and oxaliplatin (CAPOX) plus cetuximab in patients with metastatic colorectal cancer who progressed after oxaliplatin-based chemotherapy. Ann Oncol 18:305–310

    Article  CAS  PubMed  Google Scholar 

  27. Pfeiffer P, Nielsen D, Bjerregaard J et al (2008) Biweekly cetuximab and irinotecan as third-line therapy in patients with advanced colorectal cancer after failure to irinotecan, oxaliplatin and 5-fluorouracil. Ann Oncol 19:1141–1145

    Article  CAS  PubMed  Google Scholar 

  28. Gholam D, Giacchetti S, Brézault-Bonnet C et al (2006) Chronomodulated irinotecan, oxaliplatin, and leucovorin-modulated 5-fluorouracil as ambulatory salvage therapy in patients with Irinotecan- and Oxaliplatin-resistant metastatic colorectal cancer. Oncologist 11:1072–1080

    Article  CAS  PubMed  Google Scholar 

  29. Lévi F, Okyar A, Dulong S, Innominato PF, Clairambault J (2010) Circadian timing in cancer treatments. Annu Rev Pharmacol Toxicol 50:375–419

    Article  Google Scholar 

  30. Adam R, Wicherts DA, de Haas RJ et al (2009) Patients with initially unresectable colorectal liver metastases: is there a possibility of cure? J Clin Oncol 27:1829–1835

    Article  PubMed  Google Scholar 

  31. Tabernero J, Van Cutsem E, Díaz-Rubio E et al (2007) Phase II trial of cetuximab in combination with fluorouracil, leucovorin, and oxaliplatin in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 25:5225–5232

    Article  CAS  PubMed  Google Scholar 

  32. Lièvre A, Bachet JB, Boige V et al (2008) KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol 26:374–379

    Article  PubMed  Google Scholar 

  33. Cappuzzo F, Varella-Garcia M, Finocchiaro G et al (2008) Primary resistance to cetuximab therapy in EGFR FISH-positive colorectal cancer patients. Br J Cancer 99:83–89

    Article  CAS  PubMed  Google Scholar 

  34. Chung KY, Shia J, Kemeny NE et al (2005) Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol 23:1803–1810

    Article  CAS  PubMed  Google Scholar 

  35. Hebbar M, Wacrenier A, Desauw C et al (2006) Lack of usefulness of epidermal growth factor-receptor expression determination for cetuximab therapy in patients with colorectal cancer. Anticancer Drugs 17:855–857

    Article  CAS  PubMed  Google Scholar 

  36. Moroni M, Veronese S, Benvenuti S et al (2005) Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. Lancet Oncol 6:279–286

    Article  CAS  PubMed  Google Scholar 

  37. Cappuzzo F, Finocchiaro G, Rossi E et al (2008) EGFR FISH assay predicts for response to cetuximab in chemotherapy refractory colorectal cancer patients. Ann Oncol 19:717–723

    Article  CAS  PubMed  Google Scholar 

  38. Sartore-Bianchi A, Moroni M, Veronese S et al (2007) Epidermal growth factor receptor gene copy number and clinical outcome of metastatic colorectal cancer treated with panitumumab. J Clin Oncol 25:3238–3245

    Article  CAS  PubMed  Google Scholar 

  39. Milano G, Etienne-Grimaldi MC, Dahan L et al (2008) Epidermal growth factor receptor (EGFR) status and K-Ras mutations in colorectal cancer. Ann Oncol 19:2033–2038

    Article  CAS  PubMed  Google Scholar 

  40. Scartozzi M, Bearzi I, Mandolesi A et al (2009) Epidermal Growth Factor Receptor (EGFR) gene copy number (GCN) correlates with clinical activity of irinotecan-cetuximab in K-RAS wild-type colorectal cancer: a fluorescence in situ (FISH) and chromogenic in situ hybridization (CISH) analysis. BMC Cancer 9:303

    Google Scholar 

  41. Haus E, Dimitriu L, Nicolau GY et al (2001) Circadian rhythms of basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), insulin-like growth actor binding protein-3 (IGFBP-3), cortisol, and melatonin in women with breast cancer. Chronobiol Int 18:709–727

    Article  CAS  PubMed  Google Scholar 

  42. Lévi F, Filipski E, Iurisci I et al (2007) Cross-talks between circadian timing system and cell division cycle determine cancer biology and therapeutics. Cold Spring Harb Symp Quant Biol 72:465–475

    Article  PubMed  Google Scholar 

  43. Mormont MC, Waterhouse J, Bleuzen P et al (2000) Marked 24-h rest/activity rhythms are associated with better quality of life, better response, and longer survival in patients with metastatic colorectal cancer and good performance status. Clin Cancer Res 6:3038–3045

    CAS  PubMed  Google Scholar 

  44. Innominato PF, Focan C, Gorlia T, Moreau T, Garufi C, Waterhouse J, Giacchatti S, Coudert B, Iacobelli S, Genet D, Tampellini M, Chollet P, Lentz MA, Mormont MC, Levi F, Bjarnason GA, Chronotherapy Group of the European Organization for Research and Treatment of Cancer (2009) Circadian rhythm in rest and activity: a biological correlate of quality of life and a predictor of survival in patients with metastatic colorectal cancer. Cancer Res 69:4700–4707

    Google Scholar 

  45. Iurisci I, Rich T, Lévi F et al (2007) Relief of symptoms after Gefitinib is associated with improvement of rest/activity rhythm in advanced lung cancer. J Clin Oncol 25:e17–e19

    Article  PubMed  Google Scholar 

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Acknowledgments

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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Authors and Affiliations

  1. INSERM, U776 “Rythmes biologiques et cancers”, Hôpital Paul Brousse, 14 avenue Paul-Vaillant-Couturier, 94807, Villejuif Cedex, France

    Francis Lévi, Abdoulaye Karaboué, Pasquale Fabio Innominato, Sylvie Giacchetti, René Adam & Mohamed Bouchahda

  2. Univ Paris-Sud, UMR-S0776, Orsay, 91405, France

    Francis Lévi, Abdoulaye Karaboué, Pasquale Fabio Innominato, Sylvie Giacchetti & René Adam

  3. Unité de Chronothérapie, Département de Cancérologie, Centre Hépatobiliaire, Service d’Anatomie Pathologique, and Service de Biochimie, Hôpital Paul Brousse, Assistance Publique-Hôpitaux de Paris, Villejuif, 94807, France

    Francis Lévi, Abdoulaye Karaboué, Lee Gorden, Pasquale Fabio Innominato, Raphael Saffroy, Sylvie Giacchetti, Dominique Hauteville, Catherine Guettier, René Adam & Mohamed Bouchahda

  4. Departments of Surgery and Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA

    Lee Gorden

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  1. Francis Lévi
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  2. Abdoulaye Karaboué
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Correspondence to Francis Lévi.

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Lévi, F., Karaboué, A., Gorden, L. et al. Cetuximab and circadian chronomodulated chemotherapy as salvage treatment for metastatic colorectal cancer (mCRC): safety, efficacy and improved secondary surgical resectability. Cancer Chemother Pharmacol 67, 339–348 (2011). https://doi.org/10.1007/s00280-010-1327-8

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  • DOI: https://doi.org/10.1007/s00280-010-1327-8

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