Xeloda (capecitabine) - 3 Indications

Scroll down for more information on each indication:

• for the treatment of breast cancer; approved April 1998
• for the treatment of metastatic colorectal cancer; approved April 2001
• for the treatment of Dukes’ C colon cancer; approved June 2005

General Information

Xeloda (capecitabine) is a nucleoside metabolic inhibitor with antineoplastic activity.

Xeloda is specifically indicated for:

• Adjuvant Colon Cancer – Patients with Dukes’ C colon cancer
• Metastatic Colorectal Cancer - First-line as monotherapy when treatment with fluoropyrimidine therapy alone is preferred
• Metastatic Breast Cancer
  • – In combination with docetaxel after failure of prior anthracycline containing therapy
  • – As monotherapy in patients resistant to both paclitaxel and an anthracycline-containing regimen

Xeloda is supplied as tablets for oral administration. 

Standard Starting Dose

Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer)

• The recommended dose of Xeloda is 1250 mg/m2 administered orally twice daily (morning and evening; equivalent to 2500 mg/m2 total daily dose) for 2 weeks followed by a 1-week rest period given as 3-week cycles
• Adjuvant treatment in patients with Dukes’ C colon cancer is recommended for a total of 6 months [ie, Xeloda 1250 mg/m2 orally twice daily for 2 weeks followed by a 1-week rest period, given as 3-week cycles for a total of 8 cycles (24 weeks)].

In Combination With Docetaxel (Metastatic Breast Cancer)

• In combination with docetaxel, the recommended dose of Xeloda is 1250 mg/m2 twice daily for 2 weeks followed by a 1-week rest period, combined with docetaxel at 75 mg/m2 as a 1-hour intravenous infusion every 3 weeks. Pre-medication, according to the docetaxel labeling, should be started prior to docetaxel administration for patients receiving the XELODA plus docetaxel combination. See drug label for the total daily dose of Xeloda by body surface area and the number of tablets to be taken at each dose.

Mechanism of Action

Enzymes convert capecitabine to 5-fluorouracil (5-FU) in vivo. Both normal and tumor cells metabolize 5-FU to 5-fluoro-2’-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). These metabolites cause cell injury by two different mechanisms. First, FdUMP and the folate cofactor, N 5-10 -methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form a covalently bound ternary complex. This binding inhibits the formation of thymidylate from 2’-deoxyuridylate. Thymidylate is the necessary precursor of thymidine triphosphate, which is essential for the synthesis of DNA, so that a deficiency of this compound can inhibit cell division. Second, nuclear transcriptional enzymes can mistakenly incorporate FUTP in place of uridine triphosphate (UTP) during the synthesis of RNA. This metabolic error can interfere with RNA processing and protein synthesis.

Side Effects

Adverse events associated with the use of capecitabine may include (but are not limited to) the following:

• Diarrhea
• Nausea
• Vomiting
• Stomatitis
• Hand-and-foot syndrome
• Dermatitis
• Fatigue

The Xeloda drug label comes with the following Black Box Warning: Patients receiving concomitant Xeloda and oral coumarin-derivative anticoagulants such as warfarin and phenprocoumon should have their anticoagulant response (INR or prothrombin time) monitored frequently in order to adjust the anticoagulant dose accordingly. Altered coagulation parameters and/or bleeding, including death, have been reported during concomitant use. Occurrence: Within several days and up to several months after initiating Xeloda therapy; may also be seen within 1 month after stopping Xeloda. Predisposing factors: age>60 and diagnosis of cancer.

Indication 1: for the treatment of breast cancer

approved April 1998

Clinical Trial Results

The approval of Xeloda was based on a study involving 43 patients whose cancer no longer responded to conventional treatment. In that group, Xeloda appeared to help shrink tumors in 25% of patients. In a larger study of 162 patients whose cancer was resistant to normal treatment, tumors shrank by half in almost 20%.

Indication 2 - for the treatment of metastatic colorectal cancer

approved April 2001

Clinical Trial Results

The FDA's approval of Xeloda was based on results from two multi-national phase III trials involving 1,200 subjects with metastatic colorectal cancer. Results showed that Xeloda shrank tumors more effectively than a standard care of intravenous fluorouracil and leucovorin, known as the Mayo Regimen. One trial reported overall response rates to Xeloda as being more than double those to the Mayo Regimen, while in the other, the response to Xeloda was 30% greater than that to the intravenous therapy.

Indication 3 - for the treatment of Dukes’ C colon cancer

approved June 2005

Clinical Trial Results

A multicenter randomized, controlled phase 3 clinical trial in patients with Dukes’ C colon cancer (X-ACT) provided data concerning the use of Xeloda for the adjuvant treatment of patients with colon cancer. The primary objective of the study was to compare disease-free survival (DFS) in patients receiving Xeloda to those receiving IV 5-FU/LV alone. In this trial, 1987 patients were randomized either to treatment with Xeloda 1250 mg/m2 orally twice daily for 2 weeks followed by a 1-week rest period, given as 3-week cycles for a total of 8 cycles (24 weeks) or IV bolus 5-FU 425 mg/m2 and 20 mg/m2 IV leucovorin on days 1 to 5, given as 4- week cycles for a total of 6 cycles (24 weeks). All patients with normal renal function or mild renal impairment began treatment at the full starting dose of 1250 mg/m2 orally twice daily. The starting dose was reduced in patients with moderate renal impairment (calculated creatinine clearance 30 to 50 mL/min) at baseline. Subsequently, for all patients, doses were adjusted when needed according to toxicity. The median follow-up at the time of the analysis was 83 months (6.9 years). The hazard ratio for DFS for Xeloda compared to 5-FU/LV was 0.88 (95% C.I. 0.77 – 1.01). Because the upper 2-sided 95% confidence limit of hazard ratio was less than 1.20, Xeloda was non-inferior to 5-FU/LV. The choice of the non-inferiority margin of 1.20 corresponds to the retention of approximately 75% of the 5-FU/LV effect on DFS. The hazard ratio for Xeloda compared to 5-FU/LV with respect to overall survival was 0.86 (95% C.I. 0.74 – 1.01). The 5-year overall survival rates were 71.4% for Xeloda and 68.4% for 5- FU/LV.