Originally published as JCO Early Release 10.1200/JCO.2008.17.4789 on September 15 2008

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Metronomic Cyclophosphamide and Capecitabine Combined With Bevacizumab in Advanced Breast Cancer

Silvia Dellapasqua, Francesco Bertolini, Vincenzo Bagnardi, Elisabetta Campagnoli, Eloise Scarano, Rosalba Torrisi, Yuval Shaked, Patrizia Mancuso, Aron Goldhirsch, Andrea Rocca, Elisabetta Pietri, Marco Colleoni

From the Medical Senology Research Unit and Division of Medical Oncology, Department of Medicine; Division of Hematology-Oncology, Department of Medicine; and Division of Epidemiology and Biostatistics, European Institute of Oncology; Department of Statistics, University of Milan-Bicocca, Milan, Italy; Molecular and Cellular Biology Research, Sunnybrook Health Sciences Centre; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; and Oncology Institute of Southern Switzerland, Bellinzona and Lugano, Switzerland

Corresponding author: Marco Colleoni, MD, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy; e-mail: marco.colleoni{at}ieo.it

Purpose Metronomic chemotherapy has shown efficacy in patients with metastatic breast cancer. When used in association with targeted antiangiogenic drugs, it was more active than metronomic therapy alone in preclinical and clinical studies.

Patients and Methods Patients with advanced breast cancer were candidates to receive metronomic oral capecitabine (500 mg thrice daily) and cyclophosphamide (50 mg daily) plus bevacizumab (10 mg/kg every 2 weeks).

Results In 46 assessable patients, we observed one complete response (CR; 2%), 21 partial responses (PR; 46%), 19 patients (41%) with stable disease (SD), and five patients (11%) with progressive disease, for an overall response rate of 48% (95% CI, 33% to 63%). Additional long-term disease stabilization (SD 24 weeks) occurred in eight patients, for an overall clinical benefit (CR + PR + SD 24 weeks) of 68% (95% CI, 51% to 81%). Median time to progression was 42 weeks (95% CI, 26 to 72 weeks). Toxicity was generally mild. Grade 3 or 4 nonhematologic adverse effects included hypertension (n = 8), transaminitis (n = 2), and nausea/vomiting (n = 2). Higher baseline circulating endothelial cells (CECs) were correlated with overall response (P = .02), clinical benefit (P = .01), and improved progression-free survival (P = .04).

Conclusion Treatment with metronomic capecitabine and cyclophosphamide in combination with bevacizumab was effective in advanced breast cancer and was minimally toxic. The number of baseline CECs significantly correlated with response and outcome, therefore supporting further studies on this surrogate marker for the selection of patients to be candidates for antiangiogenic treatments.

published online ahead of print at www.jco.org on September 15, 2008.

Supported in part by Associazione Italiana per la Ricerca sul Cancro, Instituto Superiore di Sanitá, and the European Union Integrated Project "Angiotargeting."

Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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