Bevacizumab increases the incidence of cardiovascular events in patients with metastatic breast or colorectal cancer Accepted Manuscript Bevacizumab increases the incidence of cardiovascular events in[.]
Accepted Manuscript Bevacizumab increases the incidence of cardiovascular events in patients with metastatic breast or colorectal cancer Ioannis Kapelakis, MD, Konstantinos Toutouzas, MD, Maria Drakopoulou, MD, Archontoula Michelongona, MD, Flora Zagouri, MD, Aristotle Mpamias, MD, Paraskevi Pliatsika, MD, Meletios-Athanasios Dimopoulos, MD, Christodoulos Stefanadis, MD, Dimitrios Tousoulis, MD PII: S1109-9666(16)30236-6 DOI: 10.1016/j.hjc.2016.11.022 Reference: HJC 84 To appear in: Hellenic Journal of Cardiology Received Date: October 2016 Accepted Date: November 2016 Please cite this article as: Kapelakis I, Toutouzas K, Drakopoulou M, Michelongona A, Zagouri F, Mpamias A, Pliatsika P, Dimopoulos MA, Stefanadis C, Tousoulis D, Bevacizumab increases the incidence of cardiovascular events in patients with metastatic breast or colorectal cancer, Hellenic Journal of Cardiology (2016), doi: 10.1016/j.hjc.2016.11.022 This is a PDF file of an unedited manuscript that has been accepted for publication As a service to our customers we are providing this early version of the manuscript The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain ACCEPTED MANUSCRIPT Bevacizumab increases the incidence of cardiovascular events RI PT in patients with metastatic breast or colorectal cancer Ioannis Kapelakisa, MD, Konstantinos Toutouzasa, MD, Maria Drakopouloua, MD, SC Archontoula Michelongonaa, MD, Flora Zagourib, MD , Aristotle Mpamiasb, MD, M AN U Paraskevi Pliatsikaa, MD, Meletios-Athanasios Dimopoulosb, MD, Christodoulos Stefanadisa, MD, Dimitrios Tousoulisa, MD a TE D Department of Therapeutics, “Alexandra” Hospital, Athens Medical School, Athens, Greece Address for correspondence: EP Konstantinos Toutouzas, MD 25 Karaoli and Dimitriou str AC C b First Department of Cardiology, Athens Medical School, Athens, Greece 15562 Holargos Athens, Greece Tel (+30210)6510860 Fax (+30210)7250153 E-mail: ktoutouz@gmail.com ACCEPTED MANUSCRIPT Bevacizumab increases the incidence of cardiovascular events in patients with metastatic breast or colorectal cancer RI PT Ioannis Kapelakisa, MD, Konstantinos Toutouzasa, MD, Maria Drakopouloua, MD, Archontoula Michelongonaa, MD, Flora Zagourib, MD , Aristotle Mpamiasb, MD, Paraskevi Pliatsikaa, MD, Meletios-Athanasios Dimopoulosb, MD, Christodoulos Department of Therapeutics, “Alexandra” Hospital, Athens Medical School, Athens, Greece Address for correspondence: TE D Konstantinos Toutouzas, MD 25 Karaoli and Dimitriou str EP 15562 Holargos Athens, Greece AC C b First Department of Cardiology, Athens Medical School, Athens, Greece M AN U a SC Stefanadisa, MD, Dimitrios Tousoulisa, MD Tel (+30210)6510860 Fax (+30210)7250153 E-mail: ktoutouz@gmail.com ACCEPTED MANUSCRIPT Abstract Introduction: The effect of systemic administration of bevacizumab in treatment and comparison with the control group RI PT cancer patients in a 5-year period after the beginning of chemotherapy Methods: The study population consists of adult patients with SC metastatic breast or colorectal cancer who had not previously received any antineoplasmatic treatment Patients were stratified into two M AN U groups according to their treatment: one group was treated with conventional chemotherapy plus bevacizumab, while the other group was treated by conventional chemotherapy only The two groups did not differ in cardiovascular history and demographic characteristics TE D Results: Fatal outcomes were more frequent in the bevacizumab group, in total and in different periods of follow up as well However a statistically significant difference was noted at 12 months (P-value 0.007) EP for new deaths and at 24 (p-value 0.001) and 60 months (p-value 0.004) for deaths in total Moreover, the patients who experienced a AC C cardiovascular or thromboembolic event, belonged exclusively in bevacizumab group At 5-year follow-up, five patients of the bevacizumab group developed coronary artery disease (19.23%), four experienced an acute myocardial infarction (14.81%) and five patients suffered from thromboembolic event (17.86%) Conclusions: The addition of bevacizumab to conventional chemotherapy for metastatic breast or colorectal cancer increases the ACCEPTED MANUSCRIPT incidence of cardiovascular events mainly due to increased impact of AC C EP TE D M AN U SC RI PT myocardial infarction and thromboembolic events ACCEPTED MANUSCRIPT KEYWORDS ABBREVIATIONS VEGF Vascular Endothelial Growth Factor AMI acute myocardial infarction AC C EP TE D M AN U SC CAD coronary artery disease RI PT Bevacizumab, angiogenesis, cancer, coronary artery disease, vascular endothelial growth factor AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT ACCEPTED MANUSCRIPT Introduction Angiogenesis is a normal process involving the development of new blood vessels Essential functions such as reproduction, embryonic development and wound healing depends on the formation of new 1,2,3 In case of RI PT vessels for supplying oxygen and other nutrients inflammation, angiogenesis become excessive disrupting the balance between growth of new vessels and regression of vasculature SC Angiogenesis is a fundamental mechanism for both primary and metastatic cancer Tumor development presupposes the presence of M AN U growth factors, with Vascular Endothelia Growth Factor (VEGG) being one of the most importants contributors in tumor angiogenesis 4,5 Bevacizumab is a humanized monoclonal antibody which in combination with other chemotherapeutic drugs is approved for the treatment of TE D advanced colorectal cancer, non-small cell lung cancer, metastatic breast cancer and advanced kidney cancer 6,7,8,9 Bevacizumab binds selectively to VEGF, blocking this way the junction of the receptors to the cell EP surface 10 The most common side effects presented by the systemic administration AC C of bevacizumab, are arterial hypertension, proteinuria, thromboembolic events and bleeding but it is not clear yet the mechanism in which bevacizumab increases, for example, the incidence of thromboembolic events 11,12 Recent data proves that arterial hypertension, thromboembolic events, heart failure are usual side effects of bevacizumab, while myocardial infarction is a rare one 13 The incidence of hypertension ranges from 16% to 47% in different trials and seems to be dose dependent 14,15 16 ACCEPTED MANUSCRIPT The impact of heart failure in an incidence of 1% to 7% is more frequent when patients were previously treated with anthracycline or have undergone radiotherapy 17,18,19 Angiogenesis plays also a crucial role in atherosclerosis, being one of the characteristics of the vulnerable plaque 20 RI PT Restenosis of coronary arteries is one of the major disadvantage after implantation of stents because the intimal of the cells increase their proliferation in response to injury and inflammation 21 The fact that SC neovascularization is closely related to this restenosis and the potentials for inhibition of this process, was investigated in experimental models M AN U where stents enriched with bevacizumab were implanted and found to be safe in terms of inhibition of angiogenesis without offending endothelialisation22,23 The aim of the present study was to estimate the effect of systemic administration of bevacizumab in survival and the incidence of chemotherapy TE D cardiovascular events in surveillance of five years from the beginning of EP Material and Methods All patients were 18 years of age and older, with metastatic breast or AC C colorectal cancer and no prior systemic therapy for their malignancy The patients were divided into two groups according to the treatment selected by the oncologists .Patient suffering from breast cancer received paclitaxel 175 mg/m2 with or without bevacizumab 15 mg/kg every weeks, for 24 weeks, while patients from the same group with colorectal cancer received oxaliplatin 130 mg/m2 plus capecitabine 2000 mg/m2 with or without bevacizumab 7.5 mg/kg every weeks for the same period ACCEPTED MANUSCRIPT In present study, patients with previous chemotherapy within the last years were not included All patients were required to have adequate bone marrow, hepatic and renal function Moreover, patients with metastases in the Central Nervous System, heart failure of class II to IV RI PT according New York Heart Association, bleeding (eg, haemoptysis, gastrointestinal bleeding) within months, blood pressure that could not be controlled to less than 160/90 mmHg with medication, history of SC venous thrombosis within year, or arterial thrombosis [including cerebrovascular accident, unstable angina, acute myocardial infarction M AN U (AMI), or claudication with less than one block of exertion] within the last months or ongoing therapeutic anticoagulation, were excluded Statistical analysis of the sample was performed using the SPSS statistical package, version 15.0 (SPSS Inc, Chicago IL, USA), and Stata version 9.2 (StataCorp LP, College Station, TX, USA) In the results of the TE D study, the characteristics and incidence of cardiovascular complications or fatal outcomes are presented as recorded at each time of the evaluation, but also cumulatively at to years, for all patients and for EP two groups separately (bevacizumab group, control group) For comparing the frequencies between two groups, Fisher’s exact test was AC C used, while comparing of quantitative parameters between the two groups was done with the use of the non-parametric test by WilcoxonMann-Whitney for independent samples, due to the small size of the sample Cox proportional hazards models were used for survival analysis and event rates A p-value of