The objective of this phase II study was to determine the efficacy and safety profile of an intermittent regimen of capecitabine, administered orally to patients with breast cancer who had progressed despite prior paclitaxel therapy. In its phase I studies, capecitabine produced several objective tumor responses in heavily pretreated breast cancer patients while causing minimal bone marrow suppression. Patients who maintain a good performance status are candidates for further cytotoxic therapy. 7 This tumor-selective generation of 5-FU with low systemic exposure is hypothesized to provide an improved therapeutic ratio for capecitabine.Įffective treatment is needed for patients with metastatic breast cancer, especially those found to be paclitaxel- and anthracycline-refractory.
5 Human pharmacokinetic studies have shown that the drug is well absorbed and rapidly converted to noncytotoxic intermediates 6 and that intratumoral concentrations of 5-FU are significantly higher than plasma and normal tissue levels. 2, 4 Activity in 5-FU–refractory tumor models has also been documented. Capecitabine has demonstrated a high level of activity in preclinical xenograft models of breast, colorectal, gastric, and cervical cancer. 1 Thymidine phosphorylase occurs at higher levels in most solid tumors than in the corresponding normal tissue 2, 3 and is a tumor-associated angiogenic factor (also known as platelet-derived endothelial cell growth factor 3). The last enzymatic step, selective tumor activation of 5′-deoxy-5-fluorouridine to 5-FU, is catalyzed by thymidine phosphorylase, thus minimizing systemic exposure to 5-FU. After gastrointestinal absorption, capecitabine is hydrolyzed in the liver by carboxylesterase to produce 5′-deoxy-5-fluorocytidine, and this moiety is then deaminated on its pyrimidine ring to produce 5′-deoxy-5-fluorouridine by cytidine deaminase, an enzyme located principally in hepatic and neoplastic tissue. It has a favorable toxicity profile with the added advantage of being an oral drug administered at home.ĬAPECITABINE (XELODA Hoffman-LaRoche, Nutley, NJ), a fluoropyrimidine carbamate, was designed as an orally active drug that would deliver fluorouracil (5-FU) selectively to the tumor. Diarrhea (14%) and hand-foot syndrome (10%) were the only treatment-related adverse events that occurred with grade 3 or 4 intensity in more than 10% of patients.ĬONCLUSION: Capecitabine is an active drug in the treatment of paclitaxel-refractory metastatic breast cancer. The most common treatment-related adverse events were hand-foot syndrome, diarrhea, nausea, vomiting, and fatigue. Median duration of response was 8.1 months, median survival time was 12.8 months, and the median time to disease progression was 93 days.
Three complete responses were seen, with complete response durations of 106, 109, and 194+ days. All responding patients were resistant to or had failed paclitaxel, and all had received an anthracycline. RESULTS: The overall response rate was 20% (95% confidence interval, 14% to 28%). One hundred thirty-five patients had bidimensionally measurable disease, and 27 patients had assessable disease. One hundred sixty-three patients were entered onto the study at 25 centers, and 162 patients received capecitabine. PATIENTS AND METHODS: Patients were to have received at least two but not more than three prior chemotherapeutic regimens, one of which had to have contained paclitaxel given for metastatic disease.
This large multicenter phase II trial tested the efficacy and safety of twice-daily oral capecitabine at 2,510 mg/m 2/d given for 2 weeks followed by a 1-week rest period and repeated in 3-week cycles, in patients with paclitaxel-refractory metastatic breast cancer. PURPOSE: Capecitabine is a novel, oral, selectively tumor-activated fluoropyrimidine carbamate.