Bevacizumab increases the incidence of cardiovascular events in patients with metastatic breast or colorectal cancer

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[.]

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: 8 October 2016

Accepted Date: 7 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.

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Bevacizumab increases the incidence of cardiovascular events

in patients with metastatic breast or colorectal cancer

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

Stefanadisa, MD, Dimitrios Tousoulisa, MD

a

First Department of Cardiology, Athens Medical School, Athens, Greece

b

Department of Therapeutics, “Alexandra” Hospital, Athens Medical School, Athens, Greece

Address for correspondence:

Konstantinos Toutouzas, MD

25 Karaoli and Dimitriou str

15562 Holargos

Athens, Greece

Tel (+30210)6510860

Fax (+30210)7250153

E-mail: ktoutouz@gmail.com

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Bevacizumab increases the incidence of cardiovascular events

in patients with metastatic breast or colorectal cancer

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

Stefanadisa, MD, Dimitrios Tousoulisa, MD

a

First Department of Cardiology, Athens Medical School, Athens, Greece

b

Department of Therapeutics, “Alexandra” Hospital, Athens Medical School, Athens, Greece

Address for correspondence:

Konstantinos Toutouzas, MD

25 Karaoli and Dimitriou str

15562 Holargos

Athens, Greece

Tel (+30210)6510860

Fax (+30210)7250153

E-mail: ktoutouz@gmail.com

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Abstract

Introduction: The effect of systemic administration of bevacizumab in cancer patients in a 5-year period after the beginning of chemotherapy treatment and comparison with the control group

Methods: The study population consists of adult patients with metastatic breast or colorectal cancer who had not previously received any antineoplasmatic treatment Patients were stratified into two 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

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 12months (P-value 0.007) 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 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

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incidence of cardiovascular events mainly due to increased impact of myocardial infarction and thromboembolic events

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KEYWORDS

Bevacizumab, angiogenesis, cancer, coronary artery disease, vascular endothelial growth factor

ABBREVIATIONS

VEGF Vascular Endothelial Growth Factor

AMI acute myocardial infarction

CAD coronary artery disease

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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 vessels for supplying oxygen and other nutrients 1,2,3 In case of inflammation, angiogenesis become excessive disrupting the balance between growth of new vessels and regression of vasculature

Angiogenesis is a fundamental mechanism for both primary and metastatic cancer Tumor development presupposes the presence of 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 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 surface 10

The most common side effects presented by the systemic administration

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

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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

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 neovascularization is closely related to this restenosis and the potentials for inhibition of this process, was investigated in experimental models 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 cardiovascular events in surveillance of five years from the beginning of chemotherapy

Material and Methods

All patients were 18 years of age and older, with metastatic breast or 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 3 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 3 weeks for the same period

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In present study, patients with previous chemotherapy within the last 2 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 according New York Heart Association, bleeding (eg, haemoptysis, gastrointestinal bleeding) within 6 months, blood pressure that could not be controlled to less than 160/90 mmHg with medication, history of venous thrombosis within 1 year, or arterial thrombosis [including cerebrovascular accident, unstable angina, acute myocardial infarction (AMI), or claudication with less than one block of exertion] within the last 6 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 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 2 to 5 years, for all patients and for two groups separately (bevacizumab group, control group) For comparing the frequencies between two groups, Fisher’s exact test was used, while comparing of quantitative parameters between the two groups was done with the use of the non-parametric test by Wilcoxon-Mann-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 <0.050 was considered as statistically significant, while all measured P-values are listed in the text of the

results

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Results

The demographic characteristics, predisposal factors for atherosclerosis

and previous medication findings were similar in both groups (Table1)

Table 1 Baseline characteristics of the patients in total and in groups

Parameters

Total number of patients

[Ν=54]

Control group [Ν=16]

Bevacizumab group

[Ν=38]

p-value

Personal

history

Cardiovascular

CAD= coronary artery disease, MI = Myocardial infarction, PTCA: percutaneous transcatheter coronary angioplasty

Deaths, in the course of patient monitoring, were more frequent in

bevacizumab group in total and at any time of the evaluation, but

statistically significant difference was noted for new deaths at 12

months (P-value 0.007), and for total deaths, up to 24 months (P-value

0.001) and 60 months (P-value 0.004) as shown in Table 2 It is worth

noting that until up to 2 years follow-up, no deaths were recorded in the

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control group and 14 (41.18%) of the patients in bevacizumab group had already fatal outcomes Overall, there were 16 deaths (61.54%) and only

1 death (9.09%) up to 5 years, for bevacizumab and control groups, respectively

Table 2 Fatal outcomes

of pts

Control group

Bevacizumab

[Ν=53]*

0 (0,00) [N=16] 1 (2,70) [N=37] 0,698

[Ν=49]

0 (0,00) [N=16]

11 (33,33)

[N=16] 2 (9,09) [N=22] 0,329

[Ν=23]

1 (9,09) [N=11]

2 (16,67)

[Ν=50]

0 (0,00) [N=16]

14 (41,18)

[Ν=37]

1 (9,09) [N=11]

16 (61,54)

*Number of patients evaluated

All the patients who developed any of the non-fatal cardiovascular complications (CAD, including AMI, and thromboembolic event) were patients from the bevacizumab group (Table 3) In five years of follow

up, 5 patients of bevacizumab group (19.23%) suffered from CAD, 4 of the same group (14.81%) had an AMI and 5 (17.86%) experienced a thromboembolic event

Table 3.Cardiovascular events(except of fatal outcomes)

Bevacizumab

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[N=16] 1 (2,70) [N=37] 0,698

[N=16]

4 (12,12)

[N=16] 0 (0,00) [N=22] -

[N=11] 0 (0,00) [N=12] -

[N=16]

5 (14,71)

[N=11]

5 (19,23)

[N=16] 1 (2,70) [N=37] 0,698

[N=16] 3 (9,09) [N=33] 0,296

[N=16] 0 (0,00) [N=22] -

[N=11] 0 (0,00) [N=12] -

[N=16]

4 (11,43)

[N=11]

4 (14,81)

Thromboembolic events at 12

0 (0,00) [N=16]

5 (15,15)

Thromboembolic events at 24

0 (0,00) [N=16] 0 (0,00) [N=22] -

Thromboembolic events at 5

0 (0,00) [N=11] 1 (8,33) [N=12] 0,522

Thromboembolic events up to

0 (0,00) [N=16]

5 (14,71)

Thromboembolic events up to

0 (0,00) [N=11]

5 (17,86)

CAD=coronary artery disease, MI=myocardial infarction,*Ν: number of patients evaluated

Fatal events differed significantly (p-value=0.011) between the two groups, with fatal outcomes being in a higher incidence and having a more rapid development in the bevacizumab group (Figure 1), while there was no statistically significant difference between the two groups

in the presence of CAD (P-value 0.133), AMI (p-value 0.183) or thromboembolic event (P-value 0.131), while there was no patient from

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the control group having experienced any of the above mentioned complications

Figure 1: Patient survival in the two groups

Discussion

In this specific study, the addition of bevacizumab in the conventional chemotherapeutic scheme for the treatment of metastatic breast or colorectal cancer significantly increases the incidence of myocardial infarction, and cardiovascular events, confirming previous retrospective observations, that the risk for arterial thromboembolic events is increased in patients treated with bevacizumab

All these results, may insinuate patients with thromboembolic events in the past, including myocardial infarction, into a ‘high-risk’ group for systemic treatment of bevazicumab If these patients scheduled for treatment with bevacizumab, the administration of aspirin and statins at the same time, should be considered, in order to decrease the risk of

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CAD Moreover, the local delivery of bevacizumab at the target organ, a process already used with other antineoplasmatic drugs, might be another option for such ‘high-risk’ population Indeed, previous experimental and clinical studies have shown beneficial effect of local delivery of bevacizumab for the stabilization of vulnerable atheromatic lesions

Conclusions

Bevacizumab is a humanized monoclonal antibody which in combination with other chemotherapeutic drugs is approved for the treatment of advanced colorectal cancer,non-small cell lung cancer, metastatic breast cancer and advanced kidney cancer The addition of bevacizumab to conventional chemotherapy for metastatic cancer increases the incidence of cardiovascular events mainly due to increased impact of myocardial infarction and thromboembolic events Further investigations are needed in order to establish the exact mechanism through which bevacizumab increases the incidence of cardiovascular events