Capecitabine in colorectal cancer

Background to colorectal cancer Colorectal cancer is one of the three most commonly diagnosed cancers in the UK and western countries. A total of 13% of all cancers and 11% of all cancer-related deaths in the UK are attributable to colorectal cancer. This constitutes approximately 36,000 new patients and 16,000 deaths per year [1]. Systemic treatment options for patients with colorectal cancer have expanded rapidly over the last 10 years, with consequent improvements in the survival of those with either early-stage or advanced disease. For many years intravenous 5-fl uorouracil (5-FU), given latterly in combination with the reduced folate leucovorin (LV) [2] and often as an infusion rather than a bolus, was the only cytotoxic agent with signifi cant activity in colorectal cancer. 5-FU results in response rates of 15–25% in the metastatic setting and improves overall survival (OS) over best supportive care by 3.7 months [3]. The introduction of irinotecan and oxaliplatin into clinical practice in the late 1990s has resulted in a signifi cant improvement in both response rates and survival in patients with metastatic disease [4–7]. OS of 15–20 months has been routinely observed in large randomized trials performed over the last 5 years. Targeted anticancer agents such as bevacizumab, a monoclonal antibody that binds to and blocks the activity of VEGF, has shown activity in colorectal cancer, and when added to combination chemotherapy further improved OS to beyond 20 months [8]. Panitumumab and cetuximab belong to a second family of monoclonal antibodies, targeting the EGF receptor (EGFR), and have shown promising activity as single agents [9] or in combination with chemotherapy [10]. Chemotherapy also has an established role in the adjuvant setting, with 5-FU/LV resulting in a 25% reduction in the risk of death for patients with stage 3 tumors [11,12], and also providing a modest benefi t for those with stage 2 disease [13]. The addition of oxaliplatin to 5-FU in patients with stage 3 disease provides a further incremental improvement in disease-free survival (DFS) and OS [14,15]. The toxicity of 5-FU chemotherapy varies dependent upon the administration schedule, with hematological toxicity and diarrhea more commonly seen with bolus regimens, and hand–foot syndrome (HFS) more common with infusional schedules [16]. Infusional 5-FU-based regimens, such as the LV5FU2 regimen (LV 200 mg/m, 5-FU bolus 400 mg/m and 5-FU 600 mg/m 22-h infusion days 1 and 2, q14) have shown improved response rates and progression-free survival (PFS), as well as reduced rates of severe toxicity compared with bolus 5-FU regimens such as the Mayo clinic regimen (LV 20 mg/m, 5-FU bolus 425 mg/m, days 1–5, q28) [17]. Chemotherapy regimens of bolus 5-FU and irinotecan proved toxic, with high rates of severe toxicity and treatment-related deaths noted due to overlapping toxicity profi les [18,19]. The lower rates of severe toxicity seen with infusional 5-FU has made it the preferred drug for combination chemotherapy schedules. Schedules of 5-FU and oxaliplatin (FOLFOX) and 5-FU and irinotecan (FOLFIRI) have been developed based upon the LV5FU2 regimen. FOLFOX and FOLFIRI have similar effi cacy [20,21] and have become internationally accepted as standard fi rst-line chemotherapy options. Capecitabine is an oral pro-drug that is converted, via a three-step enzymatic pathway, into the cytotoxic drug 5-fl uorouracil. 5-fl uorouracil has an established role in the management of patients with colorectal cancer in the adjuvant and advanced disease settings. In this article we review the available clinical data for the use of capecitabine as a single agent or in combination with other cytotoxic drugs (e.g., irinotecan or oxaliplatin), or targeted anticancer treatment (e.g., anti-EGF receptor or VEGF therapy), in patients with early-stage or advanced colorectal cancer.