Metronomic Chemotherapy Combined With
Bevacizumab and Erlotinib in Patients With
Metastatic HER2-Negative Breast Cancer:
Clinical and Biological Activity
Emilia Montagna,
1
Giuseppe Cancello,
1
Vincenzo Bagnardi,
2,3
Davide Pastrello,
1
Silvia Dellapasqua,
1
Gino Perri,
1
Giuseppe Viale,
4,5
Paolo Veronesi,
5,6
Alberto Luini,
6
Mattia Intra,
6
Angelica Calleri,
7
Cristiano Rampinelli,
8
Aron Goldhirsch,
1
Francesco Bertolini,
7
Marco Colleoni
1
Abstract
The aim of this study was to determine the safety and efficacy of metronomic chemotherapy combined with
targeted drugs in patients with metastatic breast cancer (MBC). We included 26 untreated patients with
HER2-negative (HER
) MBC and poor hormone receptor expression. The analysis of the results suggests that
the metronomic chemotherapy combined with bevacizumab and erlotinib is effective and well tolerated.
Background: The object of this study was to evaluate the safety and efficacy of metronomic chemotherapy in combi-
nation with bevacizumab and erlotinib in patients with HER2-negative (HER2
-
) metastatic breast cancer (MBC) and poor
hormone receptor expression. Patients and Methods: Patients with untreated MBC were candidates to receive metro-
nomic oral capecitabine (500 mg thrice daily) and cyclophosphamide (50 mg daily) plus bevacizumab (15 mg/kg every 3
weeks) and erlotinib (100 mg daily). Results: Of 24 patients assessable for response, we observed 1 complete response
(CR, 4%), 14 partial responses (58%), 5 patients with stable disease greater than 9 weeks’ duration (SD, 21%), and 1
patient (4%) with early progression of disease. The overall clinical benefit (CB) (CR + partial response + SD 24 weeks)
was 75% (95% confidence interval [CI], 53%-90%). Median time to progression was 43 weeks (95% CI, 21-69). Patients
with low levels of circulating endothelial progenitors (CEPs) at baseline had a significantly improved progression-free
survival (PFS). Toxicity was generally mild. Grade 3 toxicity included diarrhea (n = 1), thrombosis (n = 1), and hypertension
(n = 2). Grade 2 adverse events included diarrhea (n = 5), hand-foot syndrome (n = 13), and hypertension (n = 4).
Conclusion: Treatment with metronomic chemotherapy in combination with bevacizumab and erlotinib was effective in
HER2
-
, estrogen receptor (ER)- and progesterone receptor (PR)-poor advanced breast cancer.
Clinical Breast Cancer, Vol. 12, No. 3, 207-14 © 2012 Elsevier Inc. All rights reserved.
Keywords: Bevacizumab, Erlotinib, Metronomic chemotherapy
Introduction
Preclinical studies have demonstrated an antiangiogenic action with
effective tumor control from several chemotherapeutic agents when ad-
ministered frequently at low doses (“metronomic” schedule). This ap-
proach significantly reduces toxicities and the need for growth factor
support to accelerate recovery from myelosuppression. Metronomic
chemotherapy with a low-dose oral cyclophosphamide and methotrex-
1
Department of Medicine, European Institute of Oncology, Milan, Italy
2
Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan,
Italy
3
Department of Statistics, University of Milan-Bicocca, Milan, Italy
4
Division of Pathology, European Institute of Oncology, Milan, Italy
5
University of Milan School of Medicine, Milan, Italy
6
Division of Senology, European Institute of Oncology, Milan, Italy
7
Laboratory of Hematology-Oncology, European Institute of Oncology, Milan, Italy
8
Division of Radiology, European Institute of Oncology, Milan, Italy
Submitted: Dec 21, 2011; Revised: Mar 9, 2012; Accepted: Mar 16, 2012; Epub:
April 19, 2012
Address for correspondence: Emila Montagna, MD, Department of Medicine,
Division of Medical Oncology and Unit Research of Medical Senology, European
Institute of Oncology, Milan Italy
Fax: +39.02.574829212; e-mail contact: emilia.montagna@ieo.it
Original Study
Clinical Breast Cancer June 2012 207
1526-8209/$ - see frontmatter © 2012 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.clbc.2012.03.008