During this time, many 5-FU-based regimens have been developed, including 48-h infusion or continuous infusions of 5-FU that are considered by many to be the safest and most effective. animal study Capecitabine (Xeloda?: F Hoffmann-La Roche, Basel, Switzerland) is an oral fluoropyrimidine carbamate rationally designed to generate 5-FU preferentially in tumour tissue through exploitation of higher intratumoral concentrations of thymidine phosphorylase (Miwa et al, 1998; Sch��ller et al, 2000). Human pharmacokinetic studies have shown that after oral administration, capecitabine is rapidly and almost completely absorbed through the gastrointestinal wall, thus avoiding direct intestinal exposure to 5-FU (Reigner et al, 2001). Capecitabine is then metabolised to 5-FU via a three-step enzymatic cascade.
The final stage of this conversion is mediated by thymidine phosphorylase, an enzyme present at significantly increased concentrations in a wide range of tumour types, including colorectal, breast and gastric cancers, compared with normal tissue (Miwa et al, 1998). The tumour-preferential activation of capecitabine reduces systemic exposure to 5-FU and potentially improves efficacy and safety (Sch��ller et al, 2000). As an oral agent, capecitabine enables dosing that approximates to continuous infusion 5-FU with improved convenience. Conventional infused 5-FU regimens require central venous access via a Port-a-Cath?, Hickman catheter or Groshong and the use of portable pumps, causing considerable inconvenience to patients.
In addition, the rate of complications such as thrombosis and infection is reported to be as high as 20�C60% with chronic venous access devices (Hartkamp et al, 2000; Schwarz et al, 2000). These factors, together with the known patient preference for oral chemotherapy (Liu et al, 1997; Borner et al, 2002), generated the need for an oral agent such as capecitabine that could achieve continuous exposure to 5-FU in a similar manner to infused regimens. A randomised, phase II trial in patients with advanced colorectal cancer demonstrated that capecitabine is well tolerated and has substantial antitumour activity (Van Cutsem et al, 2000). Subsequently, two multicentre, open-label, phase III studies were conducted to compare capecitabine with intravenous (i.v.
) 5-FU/leucovorin (5-FU/LV; Mayo Clinic regimen, the regulatory standard at the time), as first-line treatment for metastatic colorectal cancer (mCRC)(Hoff et al, 2001; Van Cutsem et al, 2001a). One study was conducted in Europe, Australia, Israel and Asia and the other was conducted in the USA, Canada, Brazil and Mexico. Both studies used identical protocols and an integrated analysis of all data was prospectively Carfilzomib planned. The integrated analysis has provided an opportunity to retrospectively assess the use of capecitabine in a large, well-characterised population of patients with mCRC.