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Clin Colorectal Cancer. 2015 Mar;14(1):1-10. doi: 10.1016/j.clcc.2014.11.002. Epub 2014 Nov 15.

A review of the evolution of systemic chemotherapy in the management of colorectal cancer.

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Department of Surgery, University of Gothenburg, Sahlgrenska University Hospital/Östra Institute of Clinical Sciences, Gothenburg, Sweden.
Department of Hematology and Oncology, Institut du Cancer et d'Immunogénétique (ICIG), Hôpital Paul Brousse, Assistance Publique Hôpital de Paris, Villejuif, and University Paris XI, Paris, France.
Helen F. Graham Cancer Center at Christiana Care, Newark, NJ.
European Society of Surgical Oncology, Oncosurgery Unit, HUG, Geneva, Switzerland.
European Society for Medical Oncology, Department of Oncology/Haematology, Martin Luther University, Halle, Germany.
Department of Oncology, Oslo University Hospital, Oslo, Norway.
PharmaGenesis London, London, UK. Electronic address:


Herein we present a historical review of the development of systemic chemotherapy for colorectal cancer (CRC) in the metastatic and adjuvant treatment settings. We describe the discovery of 5-fluorouracil (5-FU) by Heidelberger and colleagues in 1957, the potentiation of 5-FU cytotoxicity by the reduced folate leucovorin, and the advent of novel cytotoxic agents, including the topoisomerase I inhibitor irinotecan, the platinum-containing agent oxaliplatin, and the 5-FU prodrug capecitabine. The combination therapies, FOLFOX (5-FU/leucovorin and oxaliplatin) and FOLFIRI (5-FU/leucovorin and irinotecan), have become established as efficacious cytotoxic regimens for the treatment of metastatic CRC, resulting in overall survival times of approximately 2 years. When used as adjuvant therapy, FOLFOX also improves survival and is now the gold standard of care in this setting. Biological agents have been discovered that enhance the effect of cytotoxic therapy, including bevacizumab (a humanized monoclonal antibody that targets vascular endothelial growth factor, a central regulator of angiogenesis) and cetuximab/panitumumab (monoclonal antibodies directed against the epidermal growth factor receptor). Despite the ongoing development of novel antitumor agents and therapeutic principles as we enter the era of personalized cancer medicine, systemic chemotherapy involving infusional 5-FU/leucovorin continues to be the cornerstone of treatment for patients with CRC.


5,10-Methylenetetrahydrofolate; 5-Fluorouracil; FOLFIRI; FOLFOX; Leucovorin

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