A phase I clinical and pharmacokinetic study of capecitabine (Xeloda) and irinotecan combination therapy (XELIRI) in patients with metastatic gastrointestinal tumours.

Capecitabine is a highly active oral fluoropyrimidine that is an attractive alternative to 5-fluorouracil in colorectal cancer treatment. The current study, undertaken in 27 patients with gastrointestinal tumours, aimed to assess the toxicity and potential for significant pharmacokinetic interactions of a combination regimen incorporating capecitabine with 3-weekly irinotecan (XELIRI). Irinotecan (200 and 250 mg m(-2)) was administered as a 90-min infusion on day 1 in combination with escalating capecitabine doses (700-1250 mg m(-2) twice daily) administered on days 2-15 of a 3-week treatment cycle. Pharmacokinetics were characterised on days 1 and 2 of the first two cycles. A total of 103 treatment cycles were administered. The principal dose-limiting toxicities were diarrhoea and neutropenia. Capecitabine 1150 mg m(-2) twice daily with irinotecan 250 mg m(-2) was identified as the maximum-tolerated dose and capecitabine 1000 mg m(-2) with irinotecan 250 mg m(-2) was identified as the recommended dose for further study. Analyses confirmed that there were no significant pharmacokinetic interactions between the two agents. The combination was clinically active, with complete and partial responses achieved in heavily pretreated patients. This study indicates that XELIRI is a potentially feasible and clinically active regimen in patients with advanced gastrointestinal cancer.

Multicentre, phase II study evaluating capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer.

Treating patients with anthracycline- and taxane-pretreated metastatic breast cancer (MBC) represents a significant challenge to oncologists. The tumour-activated oral fluoropyrimidine, capecitabine, is the only treatment approved for these patients. Our study evaluated the efficacy, safety and impact on quality of life (QOL) of capecitabine in this setting. Patients (n=126) with anthracycline- and taxane-pretreated metastatic breast cancer received capecitabine 1250 mg/m(2) twice daily, days 1-14, followed by a 7-day rest period. Median time to progression was 4.9 months (95% Confidence Interval (CI): 4.0-6.4). Thirty-five patients (28%) achieved an objective response (95% CI: 20-36%), including five (4%) complete responses. Median overall survival was 15.2 months (95% CI: 13.5-19.6 months). Capecitabine demonstrated a favourable safety profile, with a low incidence of treatment-related grade 3/4 adverse events. The most common adverse events were hand-foot syndrome and gastrointestinal effects. QOL assessment showed that capecitabine treatment was associated with an increase in mean Global Health Score. Capecitabine is active, well tolerated and improves the QOL of patients with anthracycline- and taxane-pretreated metastatic breast cancer. Based on the consistently high activity demonstrated in clinical trials, capecitabine has become the reference treatment in this setting.

Phase I and pharmacokinetic study of the association of capecitabine-cisplatin in head and neck cancer patients.

The combination of cisplatin and 5-fluorouracil (5-FU) is considered to be the standard treatment in induction chemotherapy for patients with squamous cell carcinoma of the head and neck. Capecitabine (Xeloda) is an oral fluoropyrimidine that is preferentially activated at the tumoral level, exploiting the higher thymidine phosphorylase activity in tumoral tissue. This phase I trial was conducted in patients with locally recurrent or metastatic head and neck carcinoma. The treatment plan included cisplatin on day 1 every 21 days, followed by capecitabine twice daily from day 2 to day 15, with a 1-week rest period. Pharmacokinetic investigations concerned plasma measurement of unchanged capecitabine, 5'-deoxy-5-fluorocytidine, 5'-doxifluridine and 5-FU using an optimized high performance liquid chromatography method, and cisplatin measurement in plasma using a limited sampling procedure. Twenty-one patients were included (mean age 61 years, range 46-76 years). Dose (mg/m(2)) increments for cisplatin and capecitabine (b.i.d.), respectively, were as follows: level 1, 80 and 1000 (three patients); level 2, 100 and 1000 (12 patients); and level 3, 100 and 1125 (five patients). Dose-limiting toxicities occurring during the first cycle (grade >/= 3) were observed on level 2 (one patient with diarrhea, nausea, vomiting, hand-foot syndrome, one toxic death due to renal failure and neutropenia, one patient with neutropenia) and on level 3 (one patient with diarrhea, one patient with hand-foot syndrome and one patient with neutrothrombocytopenia). Due to delayed side-effects, 14 patients (67%) had repeated cycles every 28 days instead of 21 days as initially planned. Objective response was obtained in seven patients (three complete responses and four partial responses). There was no evidence of pharmacokinetic-pharmacodynamic relationships with the drugs and metabolites investigated. Combination of capecitabine and cisplatin is feasible, with a very promising response rate. The recommended doses for further phase II studies are those of level 2 with cisplatin 100 mg/m(2) on day 1 and capecitabine 1000 mg/m(2) b.i.d. on days 1-14, every 28 days.