Journal of Clinical Oncology, Vol 26, No 30 (October 20), 2008: pp. 4899-4905
© 2008 American Society of Clinical Oncology.
Metronomic Cyclophosphamide and Capecitabine Combined With Bevacizumab in Advanced Breast Cancer
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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@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.
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previously showed that the probability of prolonged CB with metronomic therapy was higher in endocrine-responsive MBC.23 These results might be related to the biology of endocrine-responsive disease, which is characterized by indolent, low-proliferating tumors and, therefore, more likely to have prolonged stabilization.27 Moreover, there is a biologic rationale for improved activity of antiangiogenic treatment in endocrine-responsive tumors.28 Several growth factors influence proliferation and survival of ER-positive hormone-resistant disease.29 In particular, VEGF is elevated in patients with endocrine-responsive disease who do not respond to hormone therapy, therefore contributing to disease progression and resistance to endocrine therapies.30-32
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We showed that baseline and viable CECs were significantly increased in patients who had a clinical response and in patients who achieved a CB. Moreover, patients who had a baseline increased apoptotic CEC count had a significantly better PFS. Flow cytometry viability studies indicated that apoptotic CEC count was related to total CEC count (data not shown). Therefore, the baseline total, viable, and apoptotic CEC count might represent an indirect measure of the angiogenic turnover and an indicator of better response to antiangiogenic therapy, supporting the use of these treatments in patients expressing high levels of baseline CECs. Further prospective trials are required to confirm the value of these data in patients who are candidates for antiangiogenic agents. If confirmed, future selection of antivascular agents should also be based on the CEC count before treatment. In conclusion, the results of this study indicate that metronomic capecitabine and cyclophosphamide combined with bevacizumab provide long-term disease control in a high proportion of patients, without significant toxicity despite prolonged use. The low burden in terms of personal costs to the patient and the possibility of continuing the treatment for up to several months in responders, as is often required in advanced breast cancer patients, support this regimen as an additional therapeutic tool in MBC patients.
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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