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Originally published as JCO Early Release 10.1200/JCO.2008.17.4789 on September 15 2008 © 2008 American Society of Clinical Oncology. Metronomic Cyclophosphamide and Capecitabine Combined With Bevacizumab in Advanced Breast Cancer
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 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.
Metronomic chemotherapy refers to the frequent, even daily, administration of chemotherapeutics at doses significantly less than the maximum-tolerated dose, with no prolonged drug-free breaks.1 An antiangiogenic activity is prominent with the protracted exposure to low doses of chemotherapeutics, if compared with their cyclic administration at the maximum-tolerated dose.2 We previously showed that the administration of oral cyclophosphamide 50 mg daily and oral methotrexate 2.5 mg twice daily 2 days per week induced a response rate (RR) of 19% and a 32% rate of clinical benefit (CB) in the absence of serious toxicity and with a marked decrease in circulating vascular endothelial growth factor (VEGF).3,4 Bevacizumab is a recombinant humanized monoclonal immunoglobulin G1 antibody against human VEGF. It binds to VEGF, preventing its interaction with the VEGF receptor tyrosine kinases VEGFR1 and VEGFR2. Preclinical studies clearly show that bevacizumab reduces tumor angiogenesis and inhibits the growth of solid tumors.5 There is a rationale and evidence for the combination of metronomic chemotherapy and targeted antiangiogenic agents like bevacizumab. In preclinical models, the combination of metronomic chemotherapy with a VEGFR2 antibody resulted in sustained regressions of large tumors, without overt toxicity occurring during the course of treatment.6 Moreover, the preclinical combination of metronomic cyclophosphamide, bevacizumab, and trastuzumab was more effective than cyclophosphamide and trastuzumab in delaying tumor growth.7 A randomized phase II trial comparing metronomic cyclophosphamide and methotrexate with the same regimen plus bevacizumab in women with pretreated advanced breast cancer was recently presented.8 A planned interim analysis after the first 19 patients per arm revealed a significant advantage in favor of the combined arm in terms of objective remissions (41%). Similarly, a combination of daily low-dose cyclophosphamide and bevacizumab was shown to induce encouraging activity in a nonrandomized phase II trial of 70 patients with recurrent ovarian cancer.9 Capecitabine has proven activity in advanced breast cancer. Retrospective analyses demonstrated that lower doses have a more favorable therapeutic index in metastatic breast cancer (MBC) when compared with standard dosage.10 Moreover, fixed daily doses and continuous (noncyclic) dosing schedules have been demonstrated to be well tolerated and active in breast cancer.11 In a phase III trial, the combination of capecitabine and bevacizumab was more active in terms of objective remissions when compared with capecitabine alone (19.8% v 9.1%, respectively; P = .001).12 A synergistic effect was observed with the metronomic combination of a fluorouracil prodrug and cyclophosphamide. In a recent preclinical study involving treatment of human advanced systemic MBC in immune-deficient mice, the combination of long-term daily low-dose cyclophosphamide and uracil-ftorafur induced long-term survival with minimal adverseeffects.13 Given these considerations, we designed a phase II trial to explore the activity and tolerability of a regimen combining metronomic cyclophosphamide (50 mg daily) plus metronomic capecitabine (500 mg thrice daily) with bevacizumab (10 mg/kg intravenous every 2 weeks). Considering the virtual absence of factors able to predict response to targeted antiangiogenic treatments, we explored the correlation of circulating endothelial cells (CECs) and circulating endothelial progenitors (CEPs) with the response and outcome of the patients.
The trial was conducted at the European Institute of Oncology, Milan, Italy. Patients age 18 to 80 years with histologically proven breast cancer with the following characteristics were eligible: pre- or postmenopausal, locally advanced (inoperable) or metastatic breast carcinoma; measurable disease; no more than three previous lines of chemotherapy for advanced disease (primary and/or adjuvant chemotherapy was allowed, as was any prior endocrine treatment); at least 4 weeks must have elapsed since prior chemotherapy or radiation therapy (6 weeks if the last regimen included mitomycin); life expectancy greater than 6 months; Eastern Cooperative Oncology Group performance status less than 2 (Karnofsky performance status > 60%); normal organ and marrow function (leukocytes  3,000/µL, absolute neutrophil count 1,500/µL, platelets 100,000/µL, total bilirubin within normal institutional limits, AST/ALT  2x institutional upper limit of normal, creatinine within normal institutional limits, or creatinine clearance 60 mL/min); absence of cerebral or leptomeningeal involvement; no history of nephritic syndrome, one positive urine dipstick reading, and proteinuria less than 150 mg/d; no severe uncontrolled hypertension; and no history of venous or arterial thromboembolic events. The trial was approved by the local ethics committee. Written informed consent was required.
Study Treatment
Study Evaluations
Biologic Correlates
Statistical Analysis
To allow early termination of the trial in case of inactive treatment, a Simon two-stage optimal design was used, minimizing the expected sample size given a poor CB. If a proportion of patients achieving a CB of Time to disease progression (TTP) was calculated from the start of treatment and evaluated using the Kaplan-Meier estimates of the survival curves. The log-rank test was used for the comparisons of survival curves between subgroups of patients. The Fisher's exact test and the Wilcoxon rank sum test were used to evaluate differences between responders and nonresponders in the distribution of categoric and continuous variables, respectively, and the log-rank test was used to evaluate the prognostic value of variables on PFS. Subgroups analyses and/or analyses of secondary end points were exploratory in nature. All P values are two-sided.
A total of 47 patients were enrolled. Forty-six patients were assessable for response and toxicity (one patient did not receive study treatment as a result of worsening of clinical conditions), and 40 patients were assessable for CB; it was too early to assess CB in six patients. Patient characteristics at baseline are listed in Table 1.
Of 46 patients assessable for response, we observed one CR (2%), 21 PRs (46%), 19 patients (41%) with SD, and five patients (11%) with progression of disease during treatment, for an overall RR of 48% (95% CI, 33% to 63%). Of 40 patients in whom the period of observation and treatment was longer than 24 weeks, we observed eight additional long-term disease stabilizations (SD > 24 weeks), for an overall CB rate (one CR + 18 PRs + eight SDs 24 weeks) of 68% (95% CI, 51% to 81%). Median TTP was 42 weeks (95% CI, 26 to 72 weeks; Fig 1). Median number of cycles per patient was 13 (range, two to 34 cycles).
Treatment was well tolerated. Main adverse effects are listed in Table 2. Grade 3 or 4 adverse effects included hypertension (n = 8), leukopenia (n = 2), neutropenia (n = 2), transaminitis (n = 2, both with liver metastases), proteinuria (n = 1), nausea (n = 1), and vomiting (n = 1). Hypertension was manageable with adequate therapy. In 14 patients, monotherapy was prescribed to control blood pressure (grade 2), whereas in eight patients, more than one drug was required (grade 3); however, no hypertensive crises were observed in the course of the trial. Proteinuria (any grade) was observed in 15 patients. Of the 46 patients who were enrolled onto the study, 23 were withdrawn as a result of disease progression, two patients refused to continue treatment within the trial, and only one patient was withdrawn from the study as a result of adverse effects (nephrotic syndrome).
At univariate analysis, hormone receptor status was significantly related to CB. CB rate was 86% (12 of 14 patients) in patients with both estrogen receptor (ER)–positive and progesterone receptor–positive disease, 71% (12 of 17 patients) in patients with ER-positive and progesterone receptor–negative disease, and 33% (three of nine patients) in patients with endocrine nonresponsive disease (P = .04). Median TTP was 49 weeks in the ER-positive cohort and 19 weeks in the ER-negative cohort (P = .002; Fig 2).
Biologic Results Baseline (before treatment) CEC count was significantly increased in patients who subsequently had a clinical response (P = .02; Fig 3A) and in patients who subsequently had a CB (P = .01; Fig 3B) compared with patients who did not. Similarly, viable CECs at baseline were significantly increased in patients who subsequently had a clinical response (P = .02, data not shown) as well as in patients who achieved a CB (P = .03, data not shown). Flow cytometry viability studies indicated that viable CEC count was correlated with the total CEC count (correlation index = 0.97, data not shown); a similar correlation was found between apoptotic CEC count and total CEC count (data not shown). Patients who had 0.27 apoptotic CECs/µL (ie, the 25th percentile distribution value) before the beginning of therapy had a significantly better PFS (P = .04; Fig 4). Patients with a CB and a clinical response also showed a trend towards a reduction in CEC count during therapy (Fig 3). The number and kinetics of CEP and of CEC subpopulations expressing VEGFR1, VEGFR2, or VEGFR3 did not significantly correlate with the clinical outcome.
MBC is a chronic disease requiring specific strategies to control the disease progression and related symptoms.16 The treatment choice is often based on evidence obtained from trials designed to investigate therapy-related issues such as whether one treatment yields better responses or longer TTP. However, few trials test treatment strategies based on the minimal burden of adverse effects necessary for reasonable control of disease. The vascular-targeted therapy approach is designed to interfere with new vessel formation, thereby slowing or preventing tumor growth. Targeted antiangiogenic drugs induce long-term changes in the tumor vasculature and are designed for continuous treatment. Similarly, chronic administration of lower doses using more frequent administration schedules of cytotoxics, without protracted breaks (metronomic delivery), has been tested to optimize the antiangiogenic effects and minimize toxicity.17,18 Preventing repair of affected tumor vessels, by such mechanisms as mobilization and incorporation of CEPs, is part of the rationale for the more frequent schedule of drug administration.19 Metronomic low-dose chemotherapy is increasingly recognized as a useful tool for the treatment of several types of cancer, such as hormone-refractory prostate cancer,20 heavily pretreated sarcoma,21 melanoma,22 ovarian cancer,9 and breast cancer.23 The clinical outcomes of antiangiogenic treatments are likely to be quite distinct from those seen with conventional cytotoxic therapies because inhibition of tumor progression with long-term stabilization of cancer, rather than rapid destruction of existing disease, may be anticipated. However, one of the most desirable end points of treatment for the individual patient with MBC is represented by the achievement of prolonged disease control (eg, CB), and strategies that can induce a CB represent an appropriate therapeutic choice. This is the first report focusing on the combination of metronomic capecitabine and cyclophosphamide combined with bevacizumab in patients with MBC. The results indicate that a clinically relevant fraction of MBC patients (68%) achieved a control of the disease for at least 6 months with this treatment strategy. Our results are in line with those achieved with other schedules of chemotherapy administered either alone or in combination with bevacizumab in patients receiving first-line treatment for MBC. In a recently published phase III trial,24 patients were randomly assigned to either paclitaxel plus bevacizumab or paclitaxel alone. The objective RR was 36.9% v 21.2% for paclitaxel plus bevacizumab versus paclitaxel alone, respectively (P < .001). These results also compare favorably with two previously reported experiences with metronomic chemotherapy alone, where CB rates of 31.7%3 and 41.5%4 were achieved. In the present study, a new schedule was designed to combine capecitabine and cyclophosphamide. This schedule has shown some confirmation of experimental efficacy. In animal models, combination therapy of capecitabine and cyclophosphamide showed synergistic antitumor activity without significant toxicity.25 Both drugs demonstrated enhanced clinical activity if combined with bevacizumab.8,12 Moreover, another fluorouracil prodrug (uracil-ftorafur), when administered in a daily low-dose manner with daily low-dose cyclophosphamide, produced significant antitumor effects in a new model of advanced MBC.13 In this study, hormone receptor status was significantly related to CB. These results are in line with previously reported data in MBC, in which endocrine-responsiveness was related to better PFS and survival.26 We 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 It is noteworthy that the CB was achieved without significant acute or delayed toxicity. In the present study, there was limited evidence of adverse effects related to classic direct cytotoxic effects (eg, significant myelotoxicity or alopecia). In fact, only 4% of the patients had grade greater than 2 leukopenia or neutropenia, and only 4% of the patients had some hair loss (Table 2). The adverse effects related to bevacizumab were, as previously reported, manageable and reversible when the treatment was stopped. The identification of patients who might benefit from targeted antiangiogenic therapies is crucial for the optimization of the treatment strategy. In the present study, we found that the baseline CEC count is a predictive biomarker of outcome that might be useful for the selection of advanced breast cancer patients who would be candidates for metronomic chemotherapy and bevacizumab. Flow cytometry studies have indicated that CECs are significantly increased in untreated cancer patients compared with healthy controls. We previously showed that, in patients with advanced breast cancer receiving metronomic chemotherapy, an increased CEC count after 2 months of therapy was a good predictor of disease-free and overall survival.33 An increased CEC count has already been reported in cancer-bearing animals treated with some antiangiogenic drugs.34,35 Previous clinical studies measured CECs during or after therapy and not at baseline as in the present study. 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.
The author(s) indicated no potential conflicts of interest.
Conception and design: Silvia Dellapasqua, Francesco Bertolini, Vincenzo Bagnardi, Elisabetta Campagnoli, Rosalba Torrisi, Patrizia Mancuso, Aron Goldhirsch, Andrea Rocca, Elisabetta Pietri, Marco Colleoni Administrative support: Eloise Scarano Provision of study materials or patients: Silvia Dellapasqua, Elisabetta Campagnoli, Patrizia Mancuso, Andrea Rocca, Elisabetta Pietri Collection and assembly of data: Silvia Dellapasqua, Francesco Bertolini, Elisabetta Campagnoli, Eloise Scarano, Rosalba Torrisi, Patrizia Mancuso, Andrea Rocca, Elisabetta Pietri Data analysis and interpretation: Silvia Dellapasqua, Francesco Bertolini, Vincenzo Bagnardi, Elisabetta Campagnoli, Eloise Scarano, Rosalba Torrisi, Yuval Shaked, Patrizia Mancuso, Aron Goldhirsch, Andrea Rocca, Elisabetta Pietri, Marco Colleoni Manuscript writing: Silvia Dellapasqua, Francesco Bertolini, Vincenzo Bagnardi, Elisabetta Campagnoli, Rosalba Torrisi, Yuval Shaked, Patrizia Mancuso, Aron Goldhirsch, Andrea Rocca, Elisabetta Pietri, Marco Colleoni Final approval of manuscript: Silvia Dellapasqua, Francesco Bertolini, Vincenzo Bagnardi, Elisabetta Campagnoli, Rosalba Torrisi, Patrizia Mancuso, Aron Goldhirsch, Andrea Rocca, Elisabetta Pietri, Marco Colleoni
We thank Robert S. Kerbel, PhD, and Urban Emmenegger, MD, for their thoughtful remarks.
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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Liang Y, Brekken RA, Hyder SM: Vascular endothelial growth factor induces proliferation of breast cancer cells and inhibits the anti-proliferative activity of anti-hormones. Endocr Relat Cancer 13:905-919, 2006 29. Wakeling AE, Nicholson RI, Gee JM: Prospects for combining hormonal and nonhormonal growth factor inhibition. Clin Cancer Res 7:S4350-S4355, 2001 (suppl 12) 30. Hyder SM, Stancel GM: Regulation of VEGF in the reproductive tract by sex-steroid hormones. Histol Histopathol 15:325-334, 2000[Medline] 31. Rydén L, Jirström K, Bendahl PO, et al: Tumor-specific expression of vascular endothelial growth factor receptor 2 but not vascular endothelial growth factor or human epidermal growth factor receptor 2 is associated with impaired response to adjuvant tamoxifen in premenopausal breast cancer. J Clin Oncol 23:4695-4704, 2005 32. Karl E, Warner K, Zeitlin B, et al: Bcl-2 acts in a proangiogenic signaling pathway through nuclear factor-kappa B and CXC chemokines. 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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
