anti-vascular endothelial growth factor therapies and

Anti-Vascular Endothelial Growth Factor Therapies andCardiovascular Toxicity: What Are the Important Clinical

Markers to Target?

CHRISTOS VAKLAVAS,a DANIEL LENIHAN,b RAZELLE KURZROCK,a APOSTOLIA MARIA TSIMBERIDOUa

aPhase 1 Program, Department of Investigational Cancer Therapeutics, and bDepartment of Cardiology,The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA

Key Words. Vascular endothelial growth factor • Antiangiogenesis • Hypertension

DisclosuresChristos Vaklavas: None; Daniel Lenihan: Consultant/advisory role: Oncomed, Immune Control; Researchfunding/contracted research: Biosite, Inc; Razelle Kurzrock: None; Apostolia Maria Tsimberidou: None.

Section editor Henk Verheul has disclosed no financial relationships relevant to the content of this article.The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and freefrom commercial bias.

LEARNING OBJECTIVES

After completing this course, the reader will be able to:

1. Promptly recognize cardiovascular adverse events associated with anti-VEGF therapy in order to formulatetreatment plans to counteract them.

2. Explain possible mechanisms by which bevacizumab, sunitinib, and sorafenib lead to cardiovascularcomplications and develop strategies for managing these complications.

3. Describe the role of RAAS in vasoconstriction and capillary rarefaction and strategize the use of RAAS inhibitionto manage these toxicities.

This article is available for continuing medical education credit at CME.TheOncologist.com.CMECME

ABSTRACT

Background. Therapies targeting vascular endothelialgrowth factor (VEGF) are associated with hyperten-sion, cardiotoxicity, and thromboembolic events.

Methods. All prospective phase I–III clinical trialspublished up to December 2008 of approved anti-VEGFtherapies (bevacizumab, sunitinib, sorafenib) and rele-vant literature were reviewed.

Results. The rates of Common Toxicity Criteria

(version 3) grade 3– 4 hypertension with bevaci-zumab, sunitinib, and sorafenib were 9.2%, 6.9%,and 7.2%, respectively. Grade 3– 4 left ventricularsystolic dysfunction was noted in 0.3%, 1.4%, and0.05% of patients, respectively, whereas the rates ofgrade 3– 4 thromboembolism were 9.6%, 1.2%, and3.8%, respectively. The renin–angiotensin–aldoste-rone system (RAAS) may play a key role in vasocon-

Correspondence: Apostolia-Maria Tsimberidou, M.D., Ph.D., The University of Texas M. D. Anderson Cancer Center, Department ofInvestigational Cancer Therapeutics, Unit 455, 1515 Holcombe Boulevard, Houston, Texas 77030, USA. Telephone: 713-792-4259; Fax:713-794-3249; e-mail: [email protected] Received October 15, 2009; accepted for publication January 18, 2010; first pub-lished online in The Oncologist Express on February 5, 2010. ©AlphaMed Press 1083-7159/2010/$30.00/0 doi: 10.1634/theoncologist.2009-0252

TheOncologist®

The Oncologist CME Program is located online at http://cme.theoncologist.com/.To take the CME activity related to this article, you must be a registered user.

Cancer Biology

The Oncologist 2010;15:130–141 www.TheOncologist.com

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striction and capillary rarefaction, which areunleashed when VEGF signaling is targeted. Inhibit-ing RAAS may be the optimal approach for managingthese toxicities.

Conclusions. In anticipation of cardiovascular com-plications with anti-VEGF therapies, early detectionand personalized management may improve clinicaloutcomes and tolerance. The Oncologist 2010;15:130–141

INTRODUCTION

Angiogenesis is a critical determinant of cancer progres-sion, because invasive growth and tumor metastasis are an-giogenesis-dependent processes [1]. The idea that blockingangiogenesis could be used as a therapeutic strategy in can-cer biology was initially implied in 1971 [2], and since then,targeting angiogenesis has become an appealing therapeu-tic approach with broad applications [3]. Vascular endothe-lial growth factor (VEGF) signaling represents a criticalstep in the process of angiogenesis [4, 5], and agents target-ing VEGF are being extensively investigated as anticancertherapies.

Cardiovascular toxicity associated with specific antian-giogenic therapies has been reported at higher than antici-pated rates and may be more prevalent when applied inunselected patient populations [6]. Constitutive VEGF signal-ing is important in normal adult cardiovascular physiology,and its abrogation by antiangiogenic therapies can result in va-soconstriction and microvascular rarefaction [7].

To date, the U.S. Food and Drug Administration (FDA)has approved bevacizumab, sunitinib, and sorafenib for anti-cancer therapy. This review focuses on these approved thera-pies, since there is clinical experience to begin to understandthe potential cardiovascular toxicity associated with their use.The optimal management of these cardiovascular adverseevents has not been defined. The purpose of this review is toincrease awareness about these complications and to discusstheir clinical significance and therapeutic interventions.

METHODS

We searched PubMed for prospective clinical trials of thecurrently FDA-approved anti-VEGF agents published up toDecember 2008, and recorded the incidences of hyperten-sion, cardiovascular toxicities, and associated clinical out-comes. Other pertinent literature and retrospective clinicaltrials were reviewed.

Reported Hypertension and Cardiotoxicity ofFDA-Approved Anti-VEGF Drugs

BevacizumabBevacizumab is a humanized monoclonal anti-VEGF anti-body composed of a human IgG1 scaffold upon which thesix complementarity-determining regions of the murine

monoclonal antibody mAb A4.6.1 are engrafted. Bevaci-zumab binds to all biologically active isoforms of VEGF-Abecause it recognizes the binding sites for VEGF receptor(VEGFR)-1 and VEGFR-2.

Hypertension. In phase I trials, bevacizumab was safelyadministered at doses up to 10 mg/kg without dose-limitingtoxicities (DLTs) [8]. Mild, nonsustained increases in bloodpressure were seen at the higher dose levels tested (3 mg/kgand 10 mg/kg) [8]. Phase I clinical trials have investigatedcombinations of bevacizumab [9–12] (Table 1). The com-bination of bevacizumab with sorafenib potentiated the hy-pertensive effects of both agents; 67% of the patientsdeveloped hypertension, half of whom had grade 3–4 tox-icity [13].

In the three phase II clinical studies that investigated thetoxicity and efficacy of single agent bevacizumab, 11.2% ofpatients developed Common Toxicity Criteria (CTC) grade�3 hypertension [14–16]. A case of hypertensive enceph-alopathy resulting in death was also described [16]. Inphase II trials of bevacizumab combined with conventionalor targeted therapies, the incidence of grade 3–4 hyperten-sion was in the range of 0%–28% [16–38]. Among patientswho received combination therapy with bevacizumab at 10mg/kg every 2 weeks or 15 mg/kg every 3 weeks, with amedian overall survival time �6 months, the combined in-cidence of grade 3 hypertension was 12.2% [19–22, 25–28,30–34, 37]. The median interval from initiation of bevaci-zumab to development of hypertension was 4.5–6 months.Patients who crossed over from the control arm to the bev-acizumab arm also developed hypertension [39, 40].

In five phase III trials, which led to the approval of be-vacizumab by the FDA, hypertension was more frequent inthe bevacizumab arms [41–45] and statistically higher infour of those five trials [41, 42, 44, 45].

Although the optimal biologic dose of bevacizumabhas not been determined, the development of hyperten-sion seems to be dose dependent. In prospective trialstesting different regimens, higher doses of bevacizumabwere associated with higher incidences of hypertension[39, 40, 46]. Also, a clear association exists between theduration of exposure to bevacizumab and the develop-ment of hypertension, as illustrated in the Bevacizumab

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Regimens: Investigation of Treatment Effects and Safetystudy [47].

Cardiotoxicity. The cardiotoxic effects of bevacizumabmay be potentiated by prior therapies associated with car-diomyopathy, such as anthracyclines [17], mitoxantrone[24], and capecitabine [48]. In a phase III study, anthracy-cline treatment preceded all cases of cardiomyopathy andheart failure (2.6% of patients) [48]. In single-agent studies,one case of myocardial infarction/heart failure was reported[16]. In phase III studies [41–45], grade 3–4 left ventricularsystolic dysfunction was reported in one study [45]. Thesestudies, however, were not designed to assess cardiac sta-tus, and events were recorded only when they were clini-cally significant. The true incidence of clinically silentreduced left ventricular ejection fraction (LVEF) or heartfailure is unknown.

Thromboembolic Events. A pooled analysis of five ran-domized trials demonstrated a higher risk for angina pecto-ris, myocardial or cerebral ischemia/infarct, or arterialthrombosis in patients treated with bevacizumab and che-

motherapy than in those treated with chemotherapy alone(3.8%, versus 1.7% in the control group; p � .05) [49]. Ameta-analysis of 15 randomized trials demonstrated that be-vacizumab was associated with a significantly higher riskfor venous thromboembolism (relative risk, 1.33; p � .001)[50].

SunitinibSunitinib is an oral antiangiogenic small molecule tyrosinekinase inhibitor. It inhibits VEGFR-1 to VEGFR-3, stemcell factor receptor, platelet-derived growth factor receptor(PDGFR)-� and PDGFR-�, RET, colony-stimulating fac-tor-1 receptor, and fetal liver tyrosine kinase receptor 3(FLT-3). It also targets VEGFR-3 signaling, which maylead to impaired angiogenic sprouting. VEGFR-3 maydrive angiogenesis when VEGFR-2 is inhibited [51] and isstimulated by VEGF-C and VEGF-D ligands, which are notneutralized by bevacizumab. By targeting PDGFR-� ex-pressed on perivascular cells, sunitinib impairs vessel sta-bilization through pericyte recruitment and maturation[52].

Table 1. Summary of grade 3–4 adverse cardiovascular events of FDA-approved anti-VEGF therapies in prospective phaseI–III clinical trials (published up to December 2008)

HypertensionLeft ventricular systolic

dysfunctionHemorrhagic/thrombotic

complications

Phase I II III Total I II III Total I II III Total

Bevacizumab

Patients 170 1,519 3,075 4,764 170 1,519 3,075 4,764 170 1,519 3,075 4,764

Events 16 157 261 434 NR 4 11 15 12 165 282 459

Average, % 9.4 10.3 8.5 9.2 NR 0.3 0.4 0.3 7.0 11.0 9.2 9.6Range, % 0–33 0–48 3–18 NR 0–12 0–3 0–18 0–32 3–23

Sunitinib

Patients 55 546 577 1178 55 546 577 1178 55 546 577 1178

Events 4 41 36 81 2a 7 7 16 3 11 NR 14

Average, % 7.3 7.5 6.2 6.9 3.6 1.3 1.2 1.4b 5.5 2.0 NR 1.2Range, % 6–8 2–18 3–8 0–13 0–5 0–2 0–13 0–4 NR

Sorafenib

Patients 446 822 748 2016 446 822 748 2016 446 822 748 2016

Events 25 98 22 145 1 NR NR 1 13 15 48 76

Average, % 6.0 12.0 3.0 7.2 0.2 NR NR 0.05 3.0 2.0 6.4 3.8Range, % 0–19 0–31 2–4 0–3 NR NR 0–14 0–8 6–7

Numbers in bold indicate cumulative average incidence for all phase I, II, and III clinical trials.aFour patients were withdrawn from a phase I study with sunitinib because of decreased LVEF [55].bIn three retrospective studies, the rates of heart failure in patients treated with sunitinib were 3%, 8%, and 15%,respectively [65, 68, 69].Abbreviations: FDA, U.S. Food and Drug Administration; LVEF, left ventricular ejection fraction; NR, not reported;VEGF, vascular endothelial growth factor.

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Hypertension. In phase I clinical trials, the incidence ofCTC grade �3 hypertension was 7.3%, and all events wererecorded at doses exceeding the maximum-tolerated dose[53–55]. In single-agent phase II clinical trials withsunitinib [56–62], the rates of grade 1–2 and grade 3 hy-pertension were 8.4% and 7.5%, respectively. In phase IIIclinical trials, which established the efficacy of sunitinib ingastrointestinal stromal tumors (GISTs) [63] and renal cellcarcinoma [64], grade 3 hypertension was more frequent inthe sunitinib group than in the placebo group (3% versus0%) [63] or the interferon group (8% versus 1%) (p � .05)[64], respectively.

A retrospective review of a phase I/II clinical trial inimatinib-refractory GISTs showed that sunitinib induceda significant increase in blood pressure within the firstcycle of treatment [65]. After four cycles of treatment,hypertension was observed in 47% (grade 3, 17%) of pa-tients [65].

Cardiotoxicity. In phase I clinical trials of sunitinib, two of55 patients developed left ventricular dysfunction and heartfailure, possibly related to treatment, and five patients ex-perienced asymptomatic reductions in LVEF [54].

In the phase II clinical trials of sunitinib in renal cell car-cinoma, 8.9% of patients developed a reduction in LVEF[56, 57]. Grade 3 reductions in LVEF were seen in a phaseIII trial of renal cell carcinoma, but the incidence was notdifferent between the sunitinib and interferon groups [64].Interferon, however, may cause cardiomyopathy by itself[66]. When sunitinib was compared with placebo in pa-tients with GISTs, the incidence of a clinically silent de-cline in LVEF associated with sunitinib was significantlyhigher [67].

In a retrospective analysis, a decline in cardiac functionwas noted in 3% of patients treated with sunitinib [68].Heart failure was preceded by hypertension in all patients,and the resultant left ventricular dysfunction was not com-pletely reversible, even upon discontinuation of sunitinib[68]. In another retrospective analysis, 11% of the patientswith GISTs had heart failure and left ventricular dysfunc-tion [65]. Notably, 18% of patients had a myocardial infarc-tion and/or asymptomatic elevations in troponin (a markerof myocardial injury) [65]. In a recent retrospective report,the maximum incidence of left ventricular dysfunction was15% [69].

Thromboembolic Events. Only a few cases of thrombo-embolic complications were reported. In phase I trials, 2 of55 patients developed myocardial infarction [54] andpulmonary embolism [53]. Two patients experiencedpulmonary embolism and one experienced cerebrovascu-

lar accident in seven phase II studies (total, 546 patients)[58, 60]. These events were rare in phase III studies [63,64].

SorafenibSorafenib is a small molecule tyrosine kinase inhibitor de-signed to inhibit C-type Raf kinase (CRAF), FLT-3, KIT,and B-type Raf kinase (BRAF). Besides targetingVEGFR-2, VEGFR-3, and PDGFR-�, it inhibits CRAF, re-sulting in interruption of the VEGF and basic fibroblastgrowth factor signaling cascades, thereby leading to a ro-bust proapoptotic effect on endothelial cells [70].

Hypertension. In phase I clinical trials of single-agent sor-afenib [71–76], the DLT was grade 3 hypertension (800 mgorally twice daily) [72]. In single-agent and combinationphase I clinical trials of sorafenib, the incidence of grade3–4 hypertension was 3% [77–82] (Table 1).

In phase II studies with sorafenib, 12% of patients de-veloped grade 1–2 and 13.8% developed grade 3 hyperten-sion [83–91]. In two concurrent phase II clinical trials ofsorafenib with interferon �-2b in renal cell carcinoma pa-tients, the rates of grade 1–2 and grade 3 hypertension were17.6% and 2%, respectively [92, 93]. Further, the additionof sorafenib to dacarbazine led to an absolute increase in therate of grade 3 hypertension of 8% (versus 0% in the dacar-bazine alone group) [94].

In a phase III trial of sorafenib versus placebo in renalcell carcinoma [95], hypertension was the most frequent se-rious adverse event, but led to drug discontinuation in �1%of patients. The incidence of hypertension was significantlyhigher than in the placebo group (sorafenib group: anygrade, 17%; grade 2, 10%; grade 3–4, 4%; placebo group:any grade, 2%; grade 2, �1%; grade 3–4, �1%) (p � .001)[95]. Similarly, in a phase III trial in hepatocellular carci-noma patients, grade 3 hypertension was more frequent inthe sorafenib arm, but the difference did not reach statisticalsignificance [96]. In a prospective study of sorafenib, a per-sistent increase in blood pressure was observed in most pa-tients within 3 weeks of treatment, and vascular stiffnessincreased significantly for up to 10 months of observation[97].

Cardiotoxicity. Serious cardiotoxicity was infrequent inthe prospective trials of sorafenib. Initially, in a phase IIItrial, the rates of cardiac ischemia/myocardial infarctionwere not statistically different in the sorafenib and placeboarms [96]. In another study, the incidences of cardiac isch-emia and infarction were significantly higher in the sor-afenib arm (renal cell carcinoma: 3% versus �1%; p � .01)[95]. In an observational study in renal cell carcinoma,




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33.8% of patients treated with sunitinib or sorafenib expe-rienced a cardiovascular event, defined as the occurrence ofincreased cardiac enzymes if normal at baseline, symptom-atic arrhythmia that required treatment, new reducedLVEF, or acute coronary syndrome [98]. An independentreview of two studies by the FDA indicated that the inci-dence of ischemia/infarction was higher in the sorafenibgroup (2.9%) than in the placebo group (0.4%) [99].

Thromboembolic Events. Sorafenib-associated throm-botic events were infrequent (phase I trials, grade 3 thromboticevents, 0.8%) [71–76]. No grade 3– 4 thromboembolicevents were noted in single-agent phase II studies or inphase III studies [83–91, 95, 96]. Two of 102 patients withrenal cell carcinoma treated with sorafenib and interferondeveloped thrombotic events in two other phase II studies[92, 93] (Table 1).

Newer anti-VEGF therapies, not yet FDA approved,have completed various phases of development (Table 2).Hypertension has been noted in clinical trials of telatinib,cediranib, VEGF Trap, vatalanib, motesanib diphosphate,and axitinib. Axitinib was also associated with cardiomy-opathy and a decline in LVEF. Thrombotic complicationswere associated with semaxinib, whereas CP-547632 wasassociated with grade 3 hypertension.

Pathophysiologic Mechanisms of CardiovascularComplications Associated with Anti-VEGFTherapy

HypertensionInhibition of VEGF signaling can cause hypertension by in-hibition of the vasomotor effects of VEGF and promotionof microvascular rarefaction.

Table 2. Selected agents in clinical development targeting VEGF and its receptors

Angiogenesis inhibitorsCompleted trials,phase Therapeutic target

Monoclonal antibodies

Bevacizumaba In phase IV trials VEGF

Soluble receptor

VEGF Trap II VEGF, PIGF, VEGF-B

Small molecule tyrosine kinaseinhibitors

Sunitinibb In phase IV trials VEGFR-1 to VEGFR-3, PDGFR-� and PDGFR-�, c-Kit, FLT-3

Sorafenibc III VEGFR-2, VEGFR-3, PDGFR-�, Raf-1, FLT-3

Vatalanib III VEGFR-1 to VEGFR-3, PDGFR-�, c-Kit

Vandetanib III VEGFR-2, EGFR, RET

Axitinib II VEGFR-1 to VEGFR-3, PDGFR, c-Kit

Motesanib diphosphate II VEGFR-1 to VEGFR-3, PDGFR, c-Kit

Cediranib II VEGFR-1 to VEGFR-3, PDGFR-�, c-Kit

Semaxinib (SU5416) II VEGFR-2, wild-type Kit, wild-type FLT-3

CP-547632 II VEGFR-2, FGFR-2

Pazopanib II VEGFR-1 to VEGFR-3, PDGFR-� and PDGFR-�, c-Kit

AEE788 II VEGFR-1 and VEGFR-2, EGFR, c-Abl, c-Src

Antisense oligonucleotides

VEGF-AS I VEGF mRNAaBevacizumab is approved by the FDA as first- and second-line treatment for metastatic colorectal cancer; first-linetreatment for nonsquamous, non-small cell lung cancer; first-line treatment in metastatic HER-2-negative breast cancer; andadvanced glioblastoma multiforme.bSunitinib is approved by the FDA for imatinib-refractory or imatinib-intolerant gastrointestinal stromal tumors andadvanced renal cell carcinoma.cSorafenib is approved by the FDA for advanced renal cell carcinoma and inoperable hepatocellular carcinoma.Abbreviations: c-Abl, c-abl oncogene 1, receptor tyrosine kinase; c-Kit, stem cell factor receptor; c-Src, v-src sarcoma viraloncogene homolog; EGFR, epidermal growth factor receptor; FDA, U.S. Food and Drug Administration; FGFR-2,fibroblast growth factor receptor 2; FLT-3, fetal liver tyrosine kinase receptor 3; HER-2, human epidermal growth factorreceptor 2; PDGFR, platelet-derived growth factor receptor; PIGF, placental growth factor; Raf-1, v-raf-1 murine leukemiaviral oncogene homolog 1; RET, REarranged during Transfection; VEGF, vascular endothelial growth factor; VEGFR,vascular endothelial growth factor receptor.



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The vasomotor effects of VEGF are mediated throughVEGFR-2. VEGFR-2 activation leads to upregulation ofendothelial nitric oxide synthase through the Src and Aktsignaling pathways. Inducible nitric oxide synthesis is ad-versely affected by therapies targeting VEGF signaling.The hypotensive effect of VEGF was highlighted in theVIVA (Vascular endothelial growth factor in Ischemia forVascular Angiogenesis) trial, in which intracoronary andi.v. recombinant human VEGF led to reductions in bloodpressure [100].

Microvascular rarefaction is the extinction of the smallblood vessels that comprise the microcirculation. It is a con-sistent feature encountered in primary and secondary hy-pertension. It has been described in individuals with agenetic propensity for high blood pressure, predating theonset of hypertension [101]. In a prospective study of bev-acizumab in metastatic colorectal cancer, after 6 months oftreatment there was a statistically significant rise in themean blood pressure and a decline in the mean dermal cap-illary density [7].

These two mechanisms by which inhibition of VEGFsignaling leads to hypertension are tightly intertwined.Elimination of constitutive baseline VEGF signaling maylead to endothelial dysfunction and vasoconstriction to theextent of nonperfusion. This functional rarefaction sets the

stage for anatomic rarefaction, that is, the frank extinctionof microvessels (Fig. 1).

VEGF is upregulated in hypertension and mediatescompensatory responses, which may be abrogated by anti-VEGF therapy. Higher levels of active circulating plasmaVEGF have been associated with a higher severity of hy-pertension and cardiovascular and cerebrovascular risk[102]. Endothelial damage, pronounced pulsatile mechani-cal stretch, hypertensive vascular remodeling, and media-tors of hypertension such as endothelin 1 and angiotensin IImay account for this association. In prospective and retro-spective studies with bevacizumab, hypertension was notedmost frequently in patients with preexisting hypertension.Intensified cardiovascular risk factor management, not lim-ited to blood pressure lowering, was associated with a de-crease in active circulating VEGF levels [102]. Thisobservation implies that cardiovascular risk factor manage-ment may blunt the hypertensive potential of antiangio-genic therapy because under such conditions, VEGF has aweaker compensatory role.

CardiotoxicityHypertension is associated with left ventricular hypertro-phy, a strong independent predictor of cardiovascular mor-bidity and mortality. Hypertensive cardiac remodeling

Figure 1. VEGF inhibition by the approved anti-VEGF therapies has differential effects on the VEGF–VEGFR axis in tumorcells and normal tissues. In noncancer tissues, endothelial dysfunction and microvascular rarefaction set the stage for the devel-opment of hypertension, cardiomyopathy, and thrombotic microangiopathy and proteinuria in the kidney (histologic pictures cour-tesy of Dr. Elsa Sotelo, University of Texas at Houston).

Abbreviations: VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.




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results in cardiomyocyte hypertrophy outgrowing capillaryexpansion. The net decline in microvascular density leadsto hypertension-associated cardiovascular events. In ani-mal models, promotion of capillary growth with VEGF re-duced apoptosis and preserved contractile function inhypertrophied, pressure-loaded hearts [103]. The potentialrisk for cardiotoxicity associated with the abrogation ofVEGF signaling has also been illustrated in mice [104].Mice with cardiomyocyte-specific deletion of the VEGFgene had fewer coronary microvessels, thinned ventricularwalls, and depressed contractile function [104]. Lastly, ex-periments in animal models have shown that the role ofVEGF signaling in normal cardiac physiology extends be-yond angiogenesis and mediates important compensatoryresponses to stress and injury [105].

Cardiac events have been observed with all approvedanti-VEGF agents. Sunitinib and sorafenib may have a di-rect toxic effect on cardiomyocytes, either by causing celldamage or by inhibiting normal repair processes. By virtueof their nonselectivity, “bystander” target kinases essentialfor cardiomyocyte survival may be inhibited [106]. Thisprocess can lead to overall myocardial cell loss as demon-strated during sunitinib administration in mice [65]. Per-haps the asymptomatic troponin elevations noted withsunitinib [65] are reflective of this process. These find-ings emphasize the need for monitoring and controllingvasoconstriction and hypertension, and protecting car-diac function.

Thromboembolic EventsVEGF plays a considerable role in the maintenance ofvascular integrity, and its abrogation is likely related toboth hemorrhage and thrombosis [107]. Selective knock-out of VEGF in endothelial cells increases apoptosis andcompromises the junctions between endothelial cells[107]. Abnormal apoptosis of endothelial cells leads to

exposure of the highly prothrombotic basement mem-brane [108]. Exposure of subendothelial von WillebrandFactor induces platelet aggregation and activation (pri-mary hemostasis), whereas exposure of tissue factor ini-tiates the coagulation cascade (secondary hemostasis)[108]. In cancer patients, tissue factor is aberrantly ex-pressed on the surface of cytokine-activated endothelialcells, monocytes, and tumor cells, contributing to theirprothrombotic propensity.

Targeting the VEGF signaling pathway can also ad-versely affect the production of platelet inhibitors, such asprostaglandin I-2 and nitric oxide [108]. VEGF releasedfrom platelets upregulates components of the fibrinolyticsystem. Although the actions of VEGF on endothelial cellsare complex, in steady-state conditions (such as seen in anadult), VEGF signaling is essential for maintaining the in-tegrity of endothelial cell junctions [107].

Anti-VEGF Therapy–Associated AdverseCardiovascular Events and Antitumor ActivityConstitutive VEGF signaling is important in normal adultcardiovascular physiology. Underlying hypertension andupregulation of RAAS seem to increase the homeostatic de-pendence of the cardiovascular system on VEGF [102, 109]because VEGF appears to mediate compensatory re-sponses. Under such conditions, the hypertensive effect ofanti-VEGF therapy may be important. Therefore, “person-alizing” cancer therapy may include understanding the roleof VEGF in any individual and, thus, predicting the ex-pected response (Table 3).

High “functional” VEGF levels in certain tumor typesmay denote dependence of tumor growth on VEGF andpredict a favorable response to anti-VEGF therapy. Thesame subset of patients, however, may be particularlysusceptible to developing cardiovascular toxicities, be-cause VEGF signaling inhibition may result in vasocon-

Table 3. Proposed theoretical paradigm for anti-VEGF therapy–associated antitumor activity and adverse cardiac events

Patientprofile

Pretherapy VEGFtumor activity

Anti-VEGF tumorresponse

Resultant bloodpressure

Expected ejectionfraction changes Comments

A 1 Yes 1 2 VEGF is a profound vasodilatorand lowers blood pressure

B Normal/2 No Unchanged Unchanged

Patient profile A is characterized by increased functional levels of VEGF and/or “favorable” VEGF genotypes. Tumorgrowth is dependent on ongoing activation of the VEGF–VEGFR axis; hence, strategies targeting this axis are a rational andeffective therapeutic approach. The same axis, however, mediates compensatory cardiovascular responses, and consequentlyanti-VEGF therapy leads more frequently to complications. Patient profile B is characterized by normal or low functionallevels of VEGF (other signaling pathways may mediate angiogenesis) and/or “unfavorable” VEGF genotypes. Tumorgrowth and cardiovascular homeostasis are less dependent on VEGF stimulation. Consequently, anti-VEGF therapies areless effective and simultaneously less toxic.Abbreviations: VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.



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striction and microvascular rarefaction. Patients withlower VEGF levels may be less likely to develop cardio-vascular toxicities and more likely to show an attenuatedantitumor response (Table 3).

New evidence suggests that genetic variability predictsclinical benefit and toxicities resulting from bevacizumabtherapy [110]. In a phase III study, certain polymorphismsin VEGF (VEGF-2578 AA and VEGF-1154 A) were asso-ciated with superior survival in the bevacizumab-contain-ing arm, but also greater susceptibility to hypertension. TheVEGF-634 CC and VEGF-1498 TT alleles were associatedwith less grade 3–4 hypertension [110], supporting the hy-pothesis that genetic predisposition contributes to anti-VEGF therapy–associated increased blood pressure, andhypertension may be a surrogate marker for antitumor ef-fect.

TREATMENT CONSIDERATIONS

Awareness of anti-VEGF therapy–associated toxicity willlead to early detection and appropriate management of su-perimposed serious cardiovascular complications. Themanagement of these complications has not been standard-ized.

A fundamental question is whether hypertension shouldbe treated with a specific therapy. Several antihypertensiveagents may be preferred on the basis of known pathophys-iologic mechanisms. Angiotensin-converting enzyme(ACE) inhibitors or angiotensin receptor blockers might bepreferential, because these RAAS inhibitors prevent heartfailure. Additionally, angiotensin II–IV (downstreamcleavage products of angiotensinogen) have significantproangiogenic effects in tumor tissues and upregulateVEGF [111]. The use of ACE inhibitors is reasonable basedon their systemic hypotensive and renoprotective effectsand their implied synergistic anti-VEGF effect in tumor tis-sues. Furthermore, ACE inhibitors are the best establishedmedicines for the prevention of heart failure.

Patients with reduced LVEF on anti-VEGF therapiesshould be closely monitored for cardiovascular events.�-blockers may be selected in the presence of symptomaticheart failure or reduced LVEF, because these agents, par-ticularly carvedilol, have a profound beneficial effect.Emerging evidence also indicates that neurohumoral stressresponses influence tumor progression and metastasis. Invivo experiments have shown that �2-adrenergic stimula-tion leads to greater tumor burden and more invasive tumorgrowth [112], making certain �-blockers a rational choicein cancer patients.

In summary, until data from prospective trials becomeavailable, the pathophysiology of angiogenesis suggests thesuperiority of inhibitors of the RAAS or the sympathetic

nervous system in the management of anti-VEGF therapy–related hypertension.

Another observation is that because proteinuria pre-cedes the onset of hypertension [113], it has potential asa screening tool for incipient cardiovascular toxicities. Itis plausible that the use of RAAS inhibitors may controlor prevent these complications. More importantly, thediscrepancy noted between the severity of the histologicchanges seen and the mild clinical manifestations seen inpatients who underwent renal biopsy while on anti-VEGF therapy emphasizes the importance of screeningand managing proteinuria. These observations, althoughnoted in patients treated with bevacizumab, may also ap-ply to patients treated with other anti-VEGF therapies.

The detection and treatment of cardiotoxicity associatedwith targeted therapies are under intense investigation. Nosingle technique can adequately predict the development ofcardiotoxicity, and the natural history of patients who de-velop these problems during anti-VEGF therapy is notestablished. In many patients, cardiotoxicity may be revers-ible upon discontinuation of the offending agents and, aftera period of stabilization, therapy may be resumed underclose collaboration with cardiovascular experts [6]. Opti-mal management of hypertension and close monitoring ofpatients previously treated with cardiotoxic chemotherapyand those with pre-existing heart disease are paramount toprevent the development of serious cardiotoxicity. Onceheart failure develops, anti-VEGF therapies should be dis-continued until the patient is stabilized on appropriate heartfailure–based therapy.

The higher risk for arterial and venous thromboem-bolic events may justify the use of aspirin in selected pa-tients treated with these agents, such as those withnormal platelet counts and platelet function, because an-ti-VEGF therapies may be associated with a low rate ofthromboembolic events. The use of aspirin in patientstreated with bevacizumab was investigated in a retro-spective pooled analysis [49]. Although among the bev-acizumab-treated patients the aspirin-treated group had ahigher incidence of arterial thrombotic events, the pa-tients receiving aspirin were more likely to have baselineprothrombotic risk factors [49]. Additionally, carefulmanagement of hyperlipidemia and other cardiovascularrisk factors should be considered; if present, the use ofstatins should be strongly entertained. In the context oftheir pleiotropic effects, a role in the prevention of ve-nous thromboembolism has recently emerged [114].

CONCLUSIONS

Agents targeting the VEGF–VEGFR axis are increasinglybeing used in cancer therapeutics. Despite their targeted na-




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ture, their use is associated with distinctive cardiovascularcomplications, including hypertension, cardiomyopathy,and thromboembolic events. These toxicities can be partic-ularly severe in patients with pre-existing cardiovascularconditions or with limited cardiovascular reserve. Asthese therapies become broadly used, cardiovascularcomplications will certainly be more frequently encoun-tered. It is possible that the development of hypertensionmay signify a meaningful antitumor effect but alsogreater propensity for cardiovascular toxicity at the sametime. Antihypertensive agents that target the RAAS maybe preferable to effectively prevent serious cardiovascu-lar adverse events. Ultimately, protecting the cardiovas-

cular system while continuing effective cancer therapywith anti-VEGF agents is the strategy most likely to im-prove patient outcomes.

AUTHOR CONTRIBUTIONSConception/Design: Apostolia Maria TsimberidouFinancial support: Apostolia Maria TsimberidouAdministrative support: Apostolia Maria Tsimberidou, Razelle KurzrockCollection and/or assembly of data: Apostolia Maria Tsimberidou,

Christos VaklavasData analysis and interpretation: Apostolia Maria Tsimberidou, Daniel

Lenihan, Christos VaklavasManuscript writing: Apostolia Maria Tsimberidou, Daniel Lenihan, ChristosVaklavasFinal approval of manuscript: Apostolia Maria Tsimberidou, Daniel

Lenihan, Razelle Kurzrock, Christos Vaklavas

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