A Review of the Evolution of Systemic Chemotherapy in the Management of Colorectal Cancer

Abstract

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.

Ursolic acid sensitized colon cancer cells to chemotherapy under hypoxia by inhibiting MDR1 through HIF-1α

“…Although the survival rates of stages I, II, and III CRC are relatively high if detected early, the prognosis of stage IV CRC is still poor, and most patients need chemotherapy because of synchronic or postoperative metastasis. Although advances in chemotherapy have occurred in the past decades, the overall response rates remain unsatisfactory (Gustavsson et al, 2015). Chemoresistance of tumors is believed to be responsible for the failure of this strategy.…”

Comparative evaluation of oncologic outcomes in colon cancer

“…CRC treatment has improved in the last decades, and overall survival has increased mainly due to the favorable effect of more efficient adjuvant chemotherapy regimens 5 . Despite the constant advances, the prognosis of CRC remains poor.…”

TAS-102: A Novel Antimetabolite for the 21st Century

“…Hence, systemic medical therapy is essential in management of these patients. Fluoropyrimidines have remained the cornerstone of therapy against colon cancer for decades [3]. Over the last decade, a number of available systemic treatments for colon cancer have increased significantly.…”