Recent years have witnessed the dramatic improvement in treatment options for patients with metastatic colorectal cancer. Prior to this the only treatment option available for patients with metastatic colorectal cancer was the combination of 5-Fluorouracil and leucovorin.
Fluorouracil showed varying pharmacokinetics and varying mode of action depending on the schedule and dosage of the drug. Because of this reason Fluorouracil was used in varying types of schedules, doses and routes. A study from Mayo Clinic had shown that the schedule of continuous infusion of 5-Fluorouracil resulted in superior response rates in metastatic colorectal cancer but had little impact on survival. Continuous infusion of Fluorouracil allowed administration of higher doses of drug without significant bone marrow suppression, but this has resulted in increase of a different set of side effects, like hand-foot-syndrome.
Modulation of the action of 5-Fluorouracil with the use of leucovorin (folinic acid) has resulted. Studies have shown that addition of leucovorin to 5-Fuoloruracil doubles the response rates in advanced colorectal cancer. (JCO 2004, 22:3766-3775).
Combination of 5-Fluorouracil and leucovorin (folinic acid) was the standard of care in the United States for treatment of patients with metastatic colorectal cancer until the year 2000. Years since then have brought newer and newer treatment options for patients with metastatic colorectal cancer. The treatment options since then includes Irinotecan (camptosar), oxaliplatin (Eloxatin), Capecitabine (Xeloda), Bevacizumab (Avastin) and Cetuximab (Erbitux).
Irinotecan (Camptosar) is a topoisomerase I inhibitor, and was first used as monotherapy by various investigators including Saltz and colleagues. The used of this drug as single agent was shown to improve survival in patients with metastatic colorectal cancer who were refractory to 5-Florouracil (Lancet 1998). Saltz and colleagues combined Irinotecan with 5-Fluorouracil and leucovorin and showed that this combination is superior to 5-Fluorouracil and leucovorin alone. Subsequently the US Food and Drugs Administration (FDA) approved this combination for the initial treatment of patients with metastatic colorectal cancer.
Oxaliplatin is a drug related to cisplatin, with mechanism of action similar to cisplatin. Oxaliplatin was evaluated in a phase III clinical trial in which the combination of 5-Fluorouracil, leucovorin and oxaliplatin (FOLFOX) was compared with combination of 5-FU and leucovorin alone. Even though this new combination showed improved response rates and improved progression free survival, overall survival was not statistically improved (JCO 2000; 18:2938-2947). Initially the US Food and Drugs Administration (FDA) refused to approve this drug due to lack of evidence for survival advantage. Many patients who were treated with oxaliplatin also had significant neurological toxicity in the form of peripheral neuropathy. Another phase III trial subsequently showed efficiency of oxaliplatin as second line treatment of metastatic colorectal cancer (JCO 2003; 21:2059-2069). This study subsequently resulted in FDA approval for oxaliplatin for second line treatment of patients with metastatic colorectal cancer. A recent phase III study has shown that FOLFOX is superior to combination of irinotecan, 5-Florouracil and leucovorin (IFL) for first line treatment of metastatic colorectal cancer (JCO 2004;22:23-30).
Bevacizumab (Avastin) is a monoclonal antibody targeted agent that targeted against the vascular endothelial growth factor (VEGF). Bevacizumab (Avastin) in combination with irinotecan 5-flourouracil and lecovorin (IFL) has recently shown to improve survival in patients with metastatic colorectal cancer when used as first line treatment (NEJM 2004;350:2335-2342). Other phase II studies have evaluated the efficacy of Bevacizumab (Avastin) incombinaiton with 5-Fluorouracil and leucovorin and showed activity is this setting as well. Based on these studies the FDA has approved Bevacizumab (Avastin) in combination with 5-flourouracil for the initial treatment of patients with metastatic colorectal cancer. A recently published study had evaluated Bevacizumab (Avastin) in combination with FOLFOX as second line treatment of patients with metastatic colorectal cancer.
Cetuximab (Erbitux) is a monoclonal antibody directed against human epidermal growth factor receptor (HER-1/EGFR). Cetuximab (Erbitux) was evaluated in combination with irinotecan in patients with irinotecan refractory metastatic colorectal cancer. This study showed a response rate of 22.5% (Proc Am Soc Clin Oncol 2001:20:2a). In subsequent studies Cetuximab (Erbitux) was shown to be effective as a single agent in patients who are refractory to irinotecan, though the response rate was higher when combined with irinotecan. the degree of response to Cetuximab (Erbitux) did not co-relate with EGFR expression as shown in the pre-clinical studies (NEJM 2004;351:337-345, JCO 2004; 22:1201-1208)
Combinations of chemotherapy and targeted agents have largely replaced the previous standard of care of 5-Fluorouracil and leucovorin in the treatment of metastatic colorectal cancer. Most active regimens for the first line treatment of metastatic colorectal cancer patients include the combination of 5-Fluorouracil, leucovorin with irinotecan or oxaliplatin, with or without Bevacizumab (Avastin) depending on individual patients. The best second line treatment regimen for patients who are progressing on this first line therapy is not very clear, and may involve combinations using Cetuximab (Erbitux).