Colorectal cancer is a worldwide public health problem, with nearly 800,000 new cases diagnosed each year resulting in approximately 500,000 deaths. In the United States, it is the second leading cause of cancer mortality, and nearly 60,000 deaths will be attributed to this disease in 2005. When diagnosed as advanced, metastatic disease, colorectal cancer is traditionally associated with a poor prognosis, with 5-year survival rates in the range of 5% to 8%. This survival rate has remained unchanged over the past 35 to 40 years. However, during the past 5 years, significant advances have been made in treatment options so that improvements in 2-year survival are now being reported, with median survival rates in the 21- to 24-month range in patients with metastatic disease. Chemotherapy has been the mainstay approach for patients with advanced colorectal cancer. For nearly 40 years, the main drug used for this disease was the fluoropyrimidine fluorouracil (5-FU). Since the late 1990s, there has been a marked increase in the number of agents that have been approved for colorectal cancer. The anticancer agents that have been approved by the United States Food and Drug Administration (FDA) include the topoisomerase I inhibitor irinotecan (Camptosar), the third-generation platinum analog oxaliplatin (Eloxatin), and the oral fluoropyrimidine capecitabine (Xeloda). In February 2004, two biologic agents were approved by the FDA: the anti-vascular endothelial growth factor (VEGF) bevacizumab (Avastin) and the anti-epidermal growth factor receptor (EGFR) antibody cetuximab (Erbitux). In this supplement to ONCOLOGY, Paulo Hoff and Scott Kopetz present a timely overview of the recent treatment advances in cytotoxic chemotherapy strategies for metastatic disease. The availability of several front-line combination regimens now makes it possible to consider tailoring therapies for individual patients based on preferences relating to oral vs intravenous medication, on patient preferences for toxicity profile, as well as on results from pharmacogenomic analyses. There are growing clinical data that the oral fluoropyrimidine capecitabine can replace infusional schedules of 5-FU/leucovorin as the backbone of combination regimens with oxaliplatin or irinotecan, leading to a marked reduction in toxicity with no compromise in clinical efficacy. In addition, there is growing evidence that the elderly patient population can be treated with the same combination therapies as younger patients with the same degree of clinical benefit and toxicity. John Marshall and Jimmy Hwang provide a nice review on the key advances that were presented at this year's annual meeting of the American Society of Clinical Oncology relating to the integration of biologic targeted agents into the routine management of patients with advanced colorectal cancer. They discuss the role of bevacizumab in combination with oxaliplatin-based chemotherapy in the first- and second-line settings and show that the addition of bevacizumab confers significant clinical benefit to cytotoxic chemotherapy without exacerbating toxicity. They review the role of EGFR as a potential target for chemotherapy and review the different anti-EGFR inhibitor compounds, including monoclonal antibodies and small molecules, that are being developed clinically for the treatment of advanced colorectal cancer. While the anti-EGFR chimeric monoclonal antibody cetuximab was initially approved for refractory disease, there is now growing focus on combining this agent with either oxaliplatin- or irinotecan-based regimens in the first- and second-line settings; the results generated thus far suggest promising clinical activity. Finally, while the incorporation of biologic agents into cytotoxic chemotherapy regimens has certainly resulted in improved clinical benefit for patients with metastatic colorectal cancer, the goal is to extend these combination regimens to the neoadjuvant and/or adjuvant setting to begin to effect real, substantive cure of patients with colorectal cancer.
Dr. Chu has acted as a consultant for and received research support from Roche, Sanofi, Pfizer, Bristol-Myers Squibb/ImClone, and Genentech.