SAFETY OF BEVACIZUMAB PLUS DOCETAXEL IN PATIENTS WITH LOCALLY RECURRENT OR METASTATIC BREAST CANCER WHO DEVELOPED BRAIN METASTASES DURING THE AVADO PHASE III STUDY
L. Y. Dirix,1 G. Romieu,2 L. Provencher,3 D. Grimes,4 L. de Souza Viana,5 A. Paterson,6 L. Mauriac,7 A. Kirsch,8 S. Pernas,9 D. W. Miles10
Oncologisch Centrum AZ-St. Augustinus Oncology, Wilrijk, Belgium;2CRLCC Val d’Aurelle, Montpellier, France; 3Hôpital du Saint-Sacrement, Quebec, Canada; 4Brisbane Haematology Oncology Clinic, Auchenflower, Australia; 5Hospital de Câncer de Barretos, Barretos, Brazil; 6Tom Baker Cancer Centre, Calgary, Canada; 7 Institut Bergonie, Bordeaux, France; 8Onkologischer Schwerpunkt Am Oskar-Helene-Heim, Berlin, Germany; 9Institut Català d’Oncologia, Barcelona, Spain;10Mount Vernon Cancer Centre, Middlesex, UK
Background: Bevacizumab (Avastin®) is a monoclonal antibody specific to vascular endothelial growth factor. The randomised, double-blind AVADO study has demonstrated that two different bevacizumab doses combined with docetaxel significantly improved progression-free survival in patients with locally recurrent (LR) or metastatic breast cancer(mBC) compared with docetaxel plus placebo; unstratified hazard ratio (HR) up to 0.72, stratified HR up to 0.61 censored for non-protocol therapy. Bevacizumab combined with docetaxel did not result in increased risk of gastrointestinal perforations, thromboembolic or bleeding events. Patients with central nervous system (CNS) metastases are currently excluded from clinical trials with bevacizumabdue to a potential risk of CNS haemorrhage. This retrospective analysis investigated the adverse events (AEs) reported in patients who developed brain metastases while participating in the AVADO trial. Methods: The AVADO study compared docetaxel 100mg/m2 plus placebo with docetaxel plus bevacizumab at either 7.5 or 15mg/kg in 736 patients with HER2-negative inoperable LR or mBC; no chemotherapy 6months prior to randomisation (≥12 months if taxane-based); Eastern Cooperative Oncology Group performance status 0–1; adequate left ventricular ejection fraction, and no CNS metastases at study entry. Docetaxel was administered every 3 weeks for up to nine cycles. Bevacizumab/placebo was administered every 3 weeks until disease progression or unacceptable toxicity. Results: Of the 730 patients inthe safety population, a total of 24 patients developed brain metastases at some point during the AVADO trial. There was no difference in the number of patients who developed brain metastases between trial arms. The mean time to development of brain metastases was 172 days with placebo, 197 days with bevacizumab 7.5mg/kg and 242 days with bevacizumab 15mg/kg. One patient receiving bevacizumab15mg/kg was diagnosed with brain metastases on day 1 and excluded from the study. No CNS bleeding AEs were reported for patients with brain metastases and other grade 3–5 AEs in these patients occurred at a similar frequency in all trial arms. Conclusions: In concordance with the overall toxicity assessment, treatment with bevacizumab did not appear to be associated with CNS haemorrhage in patientswith brain metastases. Frequency of grade 3–5 AEs was not increased in patients with brain metastases treated with bevacizumab compared with those treated with placebo. Analysis of a larger dataset may provide further information on the safety of bevacizumab therapy in patients with brain metastases.
recurrent (LR) or mBC, reporting significant improvements in efficacy compared with the taxanesalone. The combinations were generally well tolerated, with no unexpected safety findings.5–7 Commonly reported adverse events (AEs) with bevacizumab are hypertension, proteinuria and haemorrhage, most of which are grade 1–2 in severity and easily managed. Less frequent events include arterial and venous thromboembolic events, congestive heart failure (CHF), wound-healing complications and...
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