Potential of capecitabine as first-line therapy for metastatic breast cancer: dosing recommendations in patients with diminished renal function

J. A. O’Shaughnessy

Baylor-Sammons Cancer Centre, US Oncology, Dallas, TX, USA (E-mail: joyce.o’shaughnessy@usoncology.com)

The randomized phase II trial that we recently reported in this journal [1] demonstrated that the novel oral fluoropyrimidine, capecitabine, achieves similar efficacy to intravenous CMF (cyclophosphamide, methotrexate, 5-fluorouracil) in women >=55 years of age with previously untreated metastatic breast cancer. Although the trial was not powered to be able to demonstrate a significant benefit in efficacy, patients receiving capecitabine achieved a higher objective response rate with a trend towards improved time to disease progression and overall survival than patients receiving CMF. Capecitabine was tolerable in this study, with the majority of adverse events graded as mild or moderate in intensity.

Since completion of this trial, a recommendation for a reduced capecitabine starting dose in patients with moderate renal impairment at baseline (calculated creatinine clearance 30–50 ml/min) has been made, based on a retrospective analysis of data from two large trials evaluating capecitabine in patients with colorectal cancer [2]. In our trial [1], all patients received the standard capecitabine starting dose of 1250 mg/m2 twice daily for 2 weeks followed by a 1-week rest period. However, according to the new dosing guidelines, several of these patients (20%) would now receive a 25% reduction in the starting dose of capecitabine (950 mg/m2 twice daily). The median age of patients in the capecitabine-treated group was 69 years. Since calculated creatinine clearance decreases with advanced age, it could reasonably be expected that the toxicity profile observed in this trial would be improved in elderly patients who receive a reduced starting dose of capecitabine.

Capecitabine has shown considerable activity as a single agent in patients with anthracycline- and taxane-pretreated metastatic breast cancer [3, 4]. In addition, a recent, randomized, phase III trial demonstrated that the addition of capecitabine to docetaxel in patients with anthracycline-pretreated metastatic breast cancer resulted in a significant survival benefit, providing patients with a 3-month improvement in median survival [5]. The proven efficacy and tolerability of capecitabine, including the very low incidence of alopecia and myelosuppression, together with the benefits of oral administration, support further evaluation of capecitabine as early treatment for metastatic breast cancer. To this end, a randomized phase III trial is being conducted in Australia and New Zealand comparing single-agent capecitabine with the oral classical CMF regimen as first-line therapy for metastatic breast cancer. Another randomized phase III trial by the CALGB will compare capecitabine with oral classical CMF or doxorubicin/cyclophosphamide as adjuvant therapy in women >65 years old with node-positive or high-risk node-negative breast cancer. This interest in utilizing capecitabine in older women with breast cancer underscores the need for awareness of the relationship between age, calculated creatinine clearance and the safety of capecitabine.

J. A. O’Shaughnessy

Baylor-Sammons Cancer Centre, US Oncology, Dallas, TX, USA (E-mail: joyce.o’shaughnessy@usoncology.com)

References

1. O’Shaughnessy JA, Blum J, Moiseyenko V et al. Randomized, open-label, phase II trial of oral capecitabine (Xeloda®) vs. a reference arm of intravenous CMF (cyclophosphamide, methotrexate and 5-fluorouracil) as first-line therapy for advanced/metastatic breast cancer. Ann Oncol 2001; 12: 1247–1254.[Abstract]

2. Cassidy J, Twelves C, Van Cutsem E et al. First-line oral capecitabine therapy in metastatic colorectal cancer: a favorable safety profile compared with intravenous 5-fluorouracil/leucovorin. Ann Oncol 2002; 13: 566–575.[Abstract/Free Full Text]

3. Blum JL, Jones SE, Buzdar AU et al. Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 1999; 17: 485–493.[Abstract/Free Full Text]

4. Blum J, Dieras V, Lo Russo P et al. Multicenter, phase II study of capecitabine in taxane-pretreated metastatic breast carcinoma patients. Cancer 2001; 92: 1759–1768.[ISI][Medline]

5. O’Shaughnessy J, Miles D, Vukelja S et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III tria results. J Clin Oncol 2002; In press.





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