Anti-Vascular Endothelial Growth Factor Therapies and ...

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Cancer Biology Anti-Vascular Endothelial Growth Factor Therapies and Cardiovascular Toxicity: What Are the Important Clinical Markers to Target? CHRISTOS VAKLAVAS,a DANIEL LENIHAN,b RAZELLE KURZROCK,a APOSTOLIA MARIA TSIMBERIDOUa Phase 1 Program, Department of Investigational Cancer Therapeutics, and bDepartment of Cardiology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA

a

Key Words. Vascular endothelial growth factor • Antiangiogenesis • Hypertension Disclosures Christos Vaklavas: None; Daniel Lenihan: Consultant/advisory role: Oncomed, Immune Control; Research funding/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 free from 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 formulate treatment plans to counteract them. 2. Explain possible mechanisms by which bevacizumab, sunitinib, and sorafenib lead to cardiovascular complications and develop strategies for managing these complications. 3. Describe the role of RAAS in vasoconstriction and capillary rarefaction and strategize the use of RAAS inhibition to manage these toxicities. CME

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

ABSTRACT Background. Therapies targeting vascular endothelial growth factor (VEGF) are associated with hypertension, cardiotoxicity, and thromboembolic events. Methods. All prospective phase I–III clinical trials published up to December 2008 of approved anti-VEGF therapies (bevacizumab, sunitinib, sorafenib) and relevant literature were reviewed. Results. The rates of Common Toxicity Criteria

(version 3) grade 3– 4 hypertension with bevacizumab, sunitinib, and sorafenib were 9.2%, 6.9%, and 7.2%, respectively. Grade 3– 4 left ventricular systolic dysfunction was noted in 0.3%, 1.4%, and 0.05% of patients, respectively, whereas the rates of grade 3– 4 thromboembolism were 9.6%, 1.2%, and 3.8%, respectively. The renin–angiotensin–aldosterone 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 of Investigational 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 published online in The Oncologist Express on February 5, 2010. ©AlphaMed Press 1083-7159/2010/$30.00/0 doi: 10.1634/theoncologist. 2009-0252

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

Vaklavas, Lenihan, Kurzrock et al.

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striction and capillary rarefaction, which are unleashed when VEGF signaling is targeted. Inhibiting RAAS may be the optimal approach for managing these toxicities.

Conclusions. In anticipation of cardiovascular complications with anti-VEGF therapies, early detection and personalized management may improve clinical outcomes and tolerance. The Oncologist 2010;15:130 –141

INTRODUCTION

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

Angiogenesis is a critical determinant of cancer progression, because invasive growth and tumor metastasis are angiogenesis-dependent processes [1]. The idea that blocking angiogenesis could be used as a therapeutic strategy in cancer biology was initially implied in 1971 [2], and since then, targeting angiogenesis has become an appealing therapeutic approach with broad applications [3]. Vascular endothelial growth factor (VEGF) signaling represents a critical step in the process of angiogenesis [4, 5], and agents targeting VEGF are being extensively investigated as anticancer therapies. Cardiovascular toxicity associated with specific antiangiogenic therapies has been reported at higher than anticipated rates and may be more prevalent when applied in unselected patient populations [6]. Constitutive VEGF signaling is important in normal adult cardiovascular physiology, and its abrogation by antiangiogenic therapies can result in vasoconstriction and microvascular rarefaction [7]. To date, the U.S. Food and Drug Administration (FDA) has approved bevacizumab, sunitinib, and sorafenib for anticancer therapy. This review focuses on these approved therapies, since there is clinical experience to begin to understand the potential cardiovascular toxicity associated with their use. The optimal management of these cardiovascular adverse events has not been defined. The purpose of this review is to increase awareness about these complications and to discuss their clinical significance and therapeutic interventions.

METHODS We searched PubMed for prospective clinical trials of the currently FDA-approved anti-VEGF agents published up to December 2008, and recorded the incidences of hypertension, cardiovascular toxicities, and associated clinical outcomes. Other pertinent literature and retrospective clinical trials were reviewed.

Reported Hypertension and Cardiotoxicity of FDA-Approved Anti-VEGF Drugs Bevacizumab Bevacizumab is a humanized monoclonal anti-VEGF antibody composed of a human IgG1 scaffold upon which the six complementarity-determining regions of the murine

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Hypertension. In phase I trials, bevacizumab was safely administered at doses up to 10 mg/kg without dose-limiting toxicities (DLTs) [8]. Mild, nonsustained increases in blood pressure were seen at the higher dose levels tested (3 mg/kg and 10 mg/kg) [8]. Phase I clinical trials have investigated combinations of bevacizumab [9 –12] (Table 1). The combination of bevacizumab with sorafenib potentiated the hypertensive effects of both agents; 67% of the patients developed hypertension, half of whom had grade 3– 4 toxicity [13]. In the three phase II clinical studies that investigated the toxicity and efficacy of single agent bevacizumab, 11.2% of patients developed Common Toxicity Criteria (CTC) grade ⱖ3 hypertension [14 –16]. A case of hypertensive encephalopathy resulting in death was also described [16]. In phase II trials of bevacizumab combined with conventional or targeted therapies, the incidence of grade 3– 4 hypertension was in the range of 0%–28% [16 –38]. Among patients who received combination therapy with bevacizumab at 10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks, with a median overall survival time ⬎6 months, the combined incidence of grade 3 hypertension was 12.2% [19 –22, 25–28, 30 –34, 37]. The median interval from initiation of bevacizumab to development of hypertension was 4.5– 6 months. Patients who crossed over from the control arm to the bevacizumab arm also developed hypertension [39, 40]. In five phase III trials, which led to the approval of bevacizumab by the FDA, hypertension was more frequent in the bevacizumab arms [41– 45] and statistically higher in four of those five trials [41, 42, 44, 45]. Although the optimal biologic dose of bevacizumab has not been determined, the development of hypertension seems to be dose dependent. In prospective trials testing different regimens, higher doses of bevacizumab were associated with higher incidences of hypertension [39, 40, 46]. Also, a clear association exists between the duration of exposure to bevacizumab and the development of hypertension, as illustrated in the Bevacizumab

Complications of Anti-VEGF Therapies

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Table 1. Summary of grade 3– 4 adverse cardiovascular events of FDA-approved anti-VEGF therapies in prospective phase I–III clinical trials (published up to December 2008) Left ventricular systolic Hemorrhagic/thrombotic Hypertension dysfunction complications Phase Bevacizumab Patients Events Average, % Range, % Sunitinib Patients Events Average, % Range, % Sorafenib Patients Events Average, % Range, %

I

II

III

Total

I

II

III

Total

I

II

III

Total

170 16 9.4 0–33

1,519 157 10.3 0–48

3,075 261 8.5 3–18

4,764 434 9.2

170 NR NR NR

1,519 4 0.3 0–12

3,075 11 0.4 0–3

4,764 15 0.3

170 12 7.0 0–18

1,519 165 11.0 0–32

3,075 282 9.2 3–23

4,764 459 9.6

55 4 7.3 6–8

546 41 7.5 2–18

577 36 6.2 3–8

1178 81 6.9

55 2a 3.6 0–13

546 7 1.3 0–5

577 7 1.2 0–2

1178 16 1.4b

55 3 5.5 0–13

546 11 2.0 0–4

577 NR NR NR

1178 14 1.2

446 25 6.0 0–19

822 98 12.0 0–31

748 22 3.0 2–4

2016 145 7.2

446 1 0.2 0–3

822 NR NR NR

748 NR NR NR

2016 1 0.05

446 13 3.0 0–14

822 15 2.0 0–8

748 48 6.4 6–7

2016 76 3.8

Numbers in bold indicate cumulative average incidence for all phase I, II, and III clinical trials. a Four patients were withdrawn from a phase I study with sunitinib because of decreased LVEF [55]. b In 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.

Regimens: Investigation of Treatment Effects and Safety study [47]. Cardiotoxicity. The cardiotoxic effects of bevacizumab may be potentiated by prior therapies associated with cardiomyopathy, such as anthracyclines [17], mitoxantrone [24], and capecitabine [48]. In a phase III study, anthracycline treatment preceded all cases of cardiomyopathy and heart 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 ventricular systolic dysfunction was reported in one study [45]. These studies, however, were not designed to assess cardiac status, and events were recorded only when they were clinically significant. The true incidence of clinically silent reduced left ventricular ejection fraction (LVEF) or heart failure is unknown. Thromboembolic Events. A pooled analysis of five randomized trials demonstrated a higher risk for angina pectoris, myocardial or cerebral ischemia/infarct, or arterial thrombosis 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]. A meta-analysis of 15 randomized trials demonstrated that bevacizumab was associated with a significantly higher risk for venous thromboembolism (relative risk, 1.33; p ⬍ .001) [50]. Sunitinib Sunitinib is an oral antiangiogenic small molecule tyrosine kinase inhibitor. It inhibits VEGFR-1 to VEGFR-3, stem cell factor receptor, platelet-derived growth factor receptor (PDGFR)-␣ and PDGFR-␤, RET, colony-stimulating factor-1 receptor, and fetal liver tyrosine kinase receptor 3 (FLT-3). It also targets VEGFR-3 signaling, which may lead to impaired angiogenic sprouting. VEGFR-3 may drive angiogenesis when VEGFR-2 is inhibited [51] and is stimulated by VEGF-C and VEGF-D ligands, which are not neutralized by bevacizumab. By targeting PDGFR-␤ expressed on perivascular cells, sunitinib impairs vessel stabilization through pericyte recruitment and maturation [52].


Hypertension. In phase I clinical trials, the incidence of CTC grade ⱖ3 hypertension was 7.3%, and all events were recorded at doses exceeding the maximum-tolerated dose [53–55]. In single-agent phase II clinical trials with sunitinib [56 – 62], the rates of grade 1–2 and grade 3 hypertension were 8.4% and 7.5%, respectively. In phase III clinical trials, which established the efficacy of sunitinib in gastrointestinal stromal tumors (GISTs) [63] and renal cell carcinoma [64], grade 3 hypertension was more frequent in the sunitinib group than in the placebo group (3% versus 0%) [63] or the interferon group (8% versus 1%) (p ⬍ .05) [64], respectively. A retrospective review of a phase I/II clinical trial in imatinib-refractory GISTs showed that sunitinib induced a significant increase in blood pressure within the first cycle of treatment [65]. After four cycles of treatment, hypertension was observed in 47% (grade 3, 17%) of patients [65]. Cardiotoxicity. In phase I clinical trials of sunitinib, two of 55 patients developed left ventricular dysfunction and heart failure, possibly related to treatment, and five patients experienced asymptomatic reductions in LVEF [54]. In the phase II clinical trials of sunitinib in renal cell carcinoma, 8.9% of patients developed a reduction in LVEF [56, 57]. Grade 3 reductions in LVEF were seen in a phase III trial of renal cell carcinoma, but the incidence was not different between the sunitinib and interferon groups [64]. Interferon, however, may cause cardiomyopathy by itself [66]. When sunitinib was compared with placebo in patients with GISTs, the incidence of a clinically silent decline in LVEF associated with sunitinib was significantly higher [67]. In a retrospective analysis, a decline in cardiac function was 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 completely reversible, even upon discontinuation of sunitinib [68]. In another retrospective analysis, 11% of the patients with GISTs had heart failure and left ventricular dysfunction [65]. Notably, 18% of patients had a myocardial infarction and/or asymptomatic elevations in troponin (a marker of myocardial injury) [65]. In a recent retrospective report, the maximum incidence of left ventricular dysfunction was 15% [69]. Thromboembolic Events. Only a few cases of thromboembolic complications were reported. In phase I trials, 2 of 55 patients developed myocardial infarction [54] and pulmonary embolism [53]. Two patients experienced pulmonary embolism and one experienced cerebrovascu-


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lar accident in seven phase II studies (total, 546 patients) [58, 60]. These events were rare in phase III studies [63, 64]. Sorafenib Sorafenib is a small molecule tyrosine kinase inhibitor designed to inhibit C-type Raf kinase (CRAF), FLT-3, KIT, and B-type Raf kinase (BRAF). Besides targeting VEGFR-2, VEGFR-3, and PDGFR-␤, it inhibits CRAF, resulting in interruption of the VEGF and basic fibroblast growth factor signaling cascades, thereby leading to a robust proapoptotic effect on endothelial cells [70]. Hypertension. In phase I clinical trials of single-agent sorafenib [71–76], the DLT was grade 3 hypertension (800 mg orally twice daily) [72]. In single-agent and combination phase I clinical trials of sorafenib, the incidence of grade 3– 4 hypertension was 3% [77– 82] (Table 1). In phase II studies with sorafenib, 12% of patients developed grade 1–2 and 13.8% developed grade 3 hypertension [83–91]. In two concurrent phase II clinical trials of sorafenib with interferon ␣-2b in renal cell carcinoma patients, the rates of grade 1–2 and grade 3 hypertension were 17.6% and 2%, respectively [92, 93]. Further, the addition of sorafenib to dacarbazine led to an absolute increase in the rate of grade 3 hypertension of 8% (versus 0% in the dacarbazine alone group) [94]. In a phase III trial of sorafenib versus placebo in renal cell carcinoma [95], hypertension was the most frequent serious adverse event, but led to drug discontinuation in ⬍1% of patients. The incidence of hypertension was significantly higher than in the placebo group (sorafenib group: any grade, 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 carcinoma patients, grade 3 hypertension was more frequent in the sorafenib arm, but the difference did not reach statistical significance [96]. In a prospective study of sorafenib, a persistent increase in blood pressure was observed in most patients within 3 weeks of treatment, and vascular stiffness increased significantly for up to 10 months of observation [97]. Cardiotoxicity. Serious cardiotoxicity was infrequent in the prospective trials of sorafenib. Initially, in a phase III trial, the rates of cardiac ischemia/myocardial infarction were not statistically different in the sorafenib and placebo arms [96]. In another study, the incidences of cardiac ischemia and infarction were significantly higher in the sorafenib arm (renal cell carcinoma: 3% versus ⬍1%; p ⫽ .01) [95]. In an observational study in renal cell carcinoma,


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Table 2. Selected agents in clinical development targeting VEGF and its receptors Completed trials, Angiogenesis inhibitors phase Therapeutic target Monoclonal antibodies Bevacizumaba Soluble receptor VEGF Trap Small molecule tyrosine kinase inhibitors Sunitinibb Sorafenibc Vatalanib Vandetanib Axitinib Motesanib diphosphate Cediranib Semaxinib (SU5416) CP-547632 Pazopanib AEE788 Antisense oligonucleotides VEGF-AS

In phase IV trials

VEGF

II

VEGF, PIGF, VEGF-B

In phase IV trials III III III II II II II II II II

VEGFR-1 to VEGFR-3, PDGFR-␣ and PDGFR-␤, c-Kit, FLT-3 VEGFR-2, VEGFR-3, PDGFR-␤, Raf-1, FLT-3 VEGFR-1 to VEGFR-3, PDGFR-␤, c-Kit VEGFR-2, EGFR, RET VEGFR-1 to VEGFR-3, PDGFR, c-Kit VEGFR-1 to VEGFR-3, PDGFR, c-Kit VEGFR-1 to VEGFR-3, PDGFR-␤, c-Kit VEGFR-2, wild-type Kit, wild-type FLT-3 VEGFR-2, FGFR-2 VEGFR-1 to VEGFR-3, PDGFR-␣ and PDGFR-␤, c-Kit VEGFR-1 and VEGFR-2, EGFR, c-Abl, c-Src

I

VEGF mRNA

a

Bevacizumab is approved by the FDA as first- and second-line treatment for metastatic colorectal cancer; first-line treatment for nonsquamous, non-small cell lung cancer; first-line treatment in metastatic HER-2-negative breast cancer; and advanced glioblastoma multiforme. b Sunitinib is approved by the FDA for imatinib-refractory or imatinib-intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. c Sorafenib 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 viral oncogene 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 factor receptor 2; PDGFR, platelet-derived growth factor receptor; PIGF, placental growth factor; Raf-1, v-raf-1 murine leukemia viral oncogene homolog 1; RET, REarranged during Transfection; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.

33.8% of patients treated with sunitinib or sorafenib experienced a cardiovascular event, defined as the occurrence of increased cardiac enzymes if normal at baseline, symptomatic arrhythmia that required treatment, new reduced LVEF, or acute coronary syndrome [98]. An independent review of two studies by the FDA indicated that the incidence of ischemia/infarction was higher in the sorafenib group (2.9%) than in the placebo group (0.4%) [99].

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 cardiomyopathy and a decline in LVEF. Thrombotic complications were associated with semaxinib, whereas CP-547632 was associated with grade 3 hypertension.

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

Pathophysiologic Mechanisms of Cardiovascular Complications Associated with Anti-VEGF Therapy Hypertension Inhibition of VEGF signaling can cause hypertension by inhibition of the vasomotor effects of VEGF and promotion of microvascular rarefaction.


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Figure 1. VEGF inhibition by the approved anti-VEGF therapies has differential effects on the VEGF–VEGFR axis in tumor cells and normal tissues. In noncancer tissues, endothelial dysfunction and microvascular rarefaction set the stage for the development of hypertension, cardiomyopathy, and thrombotic microangiopathy and proteinuria in the kidney (histologic pictures courtesy of Dr. Elsa Sotelo, University of Texas at Houston). Abbreviations: VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.

The vasomotor effects of VEGF are mediated through VEGFR-2. VEGFR-2 activation leads to upregulation of endothelial nitric oxide synthase through the Src and Akt signaling pathways. Inducible nitric oxide synthesis is adversely affected by therapies targeting VEGF signaling. The hypotensive effect of VEGF was highlighted in the VIVA (Vascular endothelial growth factor in Ischemia for Vascular Angiogenesis) trial, in which intracoronary and i.v. recombinant human VEGF led to reductions in blood pressure [100]. Microvascular rarefaction is the extinction of the small blood vessels that comprise the microcirculation. It is a consistent feature encountered in primary and secondary hypertension. It has been described in individuals with a genetic propensity for high blood pressure, predating the onset of hypertension [101]. In a prospective study of bevacizumab in metastatic colorectal cancer, after 6 months of treatment there was a statistically significant rise in the mean blood pressure and a decline in the mean dermal capillary density [7]. These two mechanisms by which inhibition of VEGF signaling leads to hypertension are tightly intertwined. Elimination of constitutive baseline VEGF signaling may lead to endothelial dysfunction and vasoconstriction to the extent of nonperfusion. This functional rarefaction sets the


stage for anatomic rarefaction, that is, the frank extinction of microvessels (Fig. 1). VEGF is upregulated in hypertension and mediates compensatory responses, which may be abrogated by antiVEGF therapy. Higher levels of active circulating plasma VEGF have been associated with a higher severity of hypertension and cardiovascular and cerebrovascular risk [102]. Endothelial damage, pronounced pulsatile mechanical stretch, hypertensive vascular remodeling, and mediators of hypertension such as endothelin 1 and angiotensin II may account for this association. In prospective and retrospective studies with bevacizumab, hypertension was noted most frequently in patients with preexisting hypertension. Intensified cardiovascular risk factor management, not limited to blood pressure lowering, was associated with a decrease in active circulating VEGF levels [102]. This observation implies that cardiovascular risk factor management may blunt the hypertensive potential of antiangiogenic therapy because under such conditions, VEGF has a weaker compensatory role. Cardiotoxicity Hypertension is associated with left ventricular hypertrophy, a strong independent predictor of cardiovascular morbidity and mortality. Hypertensive cardiac remodeling


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Table 3. Proposed theoretical paradigm for anti-VEGF therapy–associated antitumor activity and adverse cardiac events Patient Pretherapy VEGF Anti-VEGF tumor Resultant blood Expected ejection profile tumor activity response pressure fraction changes Comments A

1

Yes

1

2

B

Normal/2

No

Unchanged

Unchanged

VEGF is a profound vasodilator and lowers blood pressure

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

results in cardiomyocyte hypertrophy outgrowing capillary expansion. The net decline in microvascular density leads to hypertension-associated cardiovascular events. In animal models, promotion of capillary growth with VEGF reduced apoptosis and preserved contractile function in hypertrophied, pressure-loaded hearts [103]. The potential risk for cardiotoxicity associated with the abrogation of VEGF signaling has also been illustrated in mice [104]. Mice with cardiomyocyte-specific deletion of the VEGF gene had fewer coronary microvessels, thinned ventricular walls, and depressed contractile function [104]. Lastly, experiments in animal models have shown that the role of VEGF signaling in normal cardiac physiology extends beyond angiogenesis and mediates important compensatory responses to stress and injury [105]. Cardiac events have been observed with all approved anti-VEGF agents. Sunitinib and sorafenib may have a direct toxic effect on cardiomyocytes, either by causing cell damage or by inhibiting normal repair processes. By virtue of their nonselectivity, “bystander” target kinases essential for cardiomyocyte survival may be inhibited [106]. This process can lead to overall myocardial cell loss as demonstrated during sunitinib administration in mice [65]. Perhaps the asymptomatic troponin elevations noted with sunitinib [65] are reflective of this process. These findings emphasize the need for monitoring and controlling vasoconstriction and hypertension, and protecting cardiac function. Thromboembolic Events VEGF plays a considerable role in the maintenance of vascular integrity, and its abrogation is likely related to both hemorrhage and thrombosis [107]. Selective knockout of VEGF in endothelial cells increases apoptosis and compromises the junctions between endothelial cells [107]. Abnormal apoptosis of endothelial cells leads to

exposure of the highly prothrombotic basement membrane [108]. Exposure of subendothelial von Willebrand Factor induces platelet aggregation and activation (primary hemostasis), whereas exposure of tissue factor initiates the coagulation cascade (secondary hemostasis) [108]. In cancer patients, tissue factor is aberrantly expressed on the surface of cytokine-activated endothelial cells, monocytes, and tumor cells, contributing to their prothrombotic propensity. Targeting the VEGF signaling pathway can also adversely affect the production of platelet inhibitors, such as prostaglandin I-2 and nitric oxide [108]. VEGF released from platelets upregulates components of the fibrinolytic system. Although the actions of VEGF on endothelial cells are complex, in steady-state conditions (such as seen in an adult), VEGF signaling is essential for maintaining the integrity of endothelial cell junctions [107].

Anti-VEGF Therapy–Associated Adverse Cardiovascular Events and Antitumor Activity Constitutive VEGF signaling is important in normal adult cardiovascular physiology. Underlying hypertension and upregulation of RAAS seem to increase the homeostatic dependence of the cardiovascular system on VEGF [102, 109] because VEGF appears to mediate compensatory responses. Under such conditions, the hypertensive effect of anti-VEGF therapy may be important. Therefore, “personalizing” cancer therapy may include understanding the role of VEGF in any individual and, thus, predicting the expected response (Table 3). High “functional” VEGF levels in certain tumor types may denote dependence of tumor growth on VEGF and predict a favorable response to anti-VEGF therapy. The same subset of patients, however, may be particularly susceptible to developing cardiovascular toxicities, because VEGF signaling inhibition may result in vasocon-


striction and microvascular rarefaction. Patients with lower VEGF levels may be less likely to develop cardiovascular toxicities and more likely to show an attenuated antitumor response (Table 3). New evidence suggests that genetic variability predicts clinical benefit and toxicities resulting from bevacizumab therapy [110]. In a phase III study, certain polymorphisms in VEGF (VEGF-2578 AA and VEGF-1154 A) were associated with superior survival in the bevacizumab-containing arm, but also greater susceptibility to hypertension. The VEGF-634 CC and VEGF-1498 TT alleles were associated with less grade 3– 4 hypertension [110], supporting the hypothesis that genetic predisposition contributes to antiVEGF therapy–associated increased blood pressure, and hypertension may be a surrogate marker for antitumor effect.

TREATMENT CONSIDERATIONS Awareness of anti-VEGF therapy–associated toxicity will lead to early detection and appropriate management of superimposed serious cardiovascular complications. The management of these complications has not been standardized. A fundamental question is whether hypertension should be treated with a specific therapy. Several antihypertensive agents may be preferred on the basis of known pathophysiologic mechanisms. Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers might be preferential, because these RAAS inhibitors prevent heart failure. Additionally, angiotensin II–IV (downstream cleavage products of angiotensinogen) have significant proangiogenic effects in tumor tissues and upregulate VEGF [111]. The use of ACE inhibitors is reasonable based on their systemic hypotensive and renoprotective effects and their implied synergistic anti-VEGF effect in tumor tissues. Furthermore, ACE inhibitors are the best established medicines for the prevention of heart failure. Patients with reduced LVEF on anti-VEGF therapies should be closely monitored for cardiovascular events. ␤-blockers may be selected in the presence of symptomatic heart failure or reduced LVEF, because these agents, particularly carvedilol, have a profound beneficial effect. Emerging evidence also indicates that neurohumoral stress responses influence tumor progression and metastasis. In vivo experiments have shown that ␤2-adrenergic stimulation leads to greater tumor burden and more invasive tumor growth [112], making certain ␤-blockers a rational choice in cancer patients. In summary, until data from prospective trials become available, the pathophysiology of angiogenesis suggests the superiority of inhibitors of the RAAS or the sympathetic


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nervous system in the management of anti-VEGF therapy– related hypertension. Another observation is that because proteinuria precedes the onset of hypertension [113], it has potential as a screening tool for incipient cardiovascular toxicities. It is plausible that the use of RAAS inhibitors may control or prevent these complications. More importantly, the discrepancy noted between the severity of the histologic changes seen and the mild clinical manifestations seen in patients who underwent renal biopsy while on antiVEGF therapy emphasizes the importance of screening and managing proteinuria. These observations, although noted in patients treated with bevacizumab, may also apply to patients treated with other anti-VEGF therapies. The detection and treatment of cardiotoxicity associated with targeted therapies are under intense investigation. No single technique can adequately predict the development of cardiotoxicity, and the natural history of patients who develop these problems during anti-VEGF therapy is not established. In many patients, cardiotoxicity may be reversible upon discontinuation of the offending agents and, after a period of stabilization, therapy may be resumed under close collaboration with cardiovascular experts [6]. Optimal management of hypertension and close monitoring of patients previously treated with cardiotoxic chemotherapy and those with pre-existing heart disease are paramount to prevent the development of serious cardiotoxicity. Once heart failure develops, anti-VEGF therapies should be discontinued until the patient is stabilized on appropriate heart failure– based therapy. The higher risk for arterial and venous thromboembolic events may justify the use of aspirin in selected patients treated with these agents, such as those with normal platelet counts and platelet function, because anti-VEGF therapies may be associated with a low rate of thromboembolic events. The use of aspirin in patients treated with bevacizumab was investigated in a retrospective pooled analysis [49]. Although among the bevacizumab-treated patients the aspirin-treated group had a higher incidence of arterial thrombotic events, the patients receiving aspirin were more likely to have baseline prothrombotic risk factors [49]. Additionally, careful management of hyperlipidemia and other cardiovascular risk factors should be considered; if present, the use of statins should be strongly entertained. In the context of their pleiotropic effects, a role in the prevention of venous thromboembolism has recently emerged [114].

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


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ture, their use is associated with distinctive cardiovascular complications, including hypertension, cardiomyopathy, and thromboembolic events. These toxicities can be particularly severe in patients with pre-existing cardiovascular conditions or with limited cardiovascular reserve. As these therapies become broadly used, cardiovascular complications will certainly be more frequently encountered. It is possible that the development of hypertension may signify a meaningful antitumor effect but also greater propensity for cardiovascular toxicity at the same time. Antihypertensive agents that target the RAAS may be preferable to effectively prevent serious cardiovascular adverse events. Ultimately, protecting the cardiovas-

cular system while continuing effective cancer therapy with anti-VEGF agents is the strategy most likely to improve patient outcomes.

REFERENCES

14

Siegel AB, Cohen EI, Ocean A et al. Phase II trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma. J Clin Oncol 2008;26:2992–2998.

15

Burger RA, Sill MW, Monk BJ, Greer BE, Sorosky JI. Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: A Gynecologic Oncology Group study. J Clin Oncol 2007;25:5165–5171.

16

Cannistra SA, Matulonis UA, Penson RT et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol 2007;25:5180 –5186.

17

D’Adamo DR, Anderson SE, Albritton K et al. Phase II study of doxorubicin and bevacizumab for patients with metastatic soft-tissue sarcomas. J Clin Oncol 2005;23:7135–7142.

18

Emmanouilides C, Sfakiotaki G, Androulakis N et al. Front-line bevacizumab in combination with oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) in patients with metastatic colorectal cancer: A multicenter phase II study. BMC Cancer 2007;7:91.

19

Garcia AA, Hirte H, Fleming G et al. Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: A trial of the California, Chicago, and Princess Margaret Hospital phase II consortia. J Clin Oncol 2008;26:76 – 82.

20

Giantonio BJ, Levy DE, O’Dwyer PJ et al. A phase II study of high-dose bevacizumab in combination with irinotecan, 5-fluorouracil, leucovorin, as initial therapy for advanced colorectal cancer: Results from the Eastern Cooperative Oncology Group study E2200. Ann Oncol 2006;17:1399 – 1403.

21

Hainsworth JD, Sosman JA, Spigel DR et al. Treatment of metastatic renal cell carcinoma with a combination of bevacizumab and erlotinib. J Clin Oncol 2005;23:7889 –7896.

22

Hainsworth JD, Spigel DR, Farley C et al. Phase II trial of bevacizumab and erlotinib in carcinomas of unknown primary site: The Minnie Pearl Cancer Research Network. J Clin Oncol 2007;25:1747–1752.

23

Jackman DM, Kindler HL, Yeap BY et al. Erlotinib plus bevacizumab in previously treated patients with malignant pleural mesothelioma. Cancer 2008;113:808 – 814.

24

Karp JE, Gojo I, Pili R et al. Targeting vascular endothelial growth factor for relapsed and refractory adult acute myelogenous leukemias: Therapy with sequential 1-beta-d-arabinofuranosylcytosine, mitoxantrone, and bevacizumab. Clin Cancer Res 2004;10:3577–3585.

25

Kindler HL, Friberg G, Singh DA et al. Phase II trial of bevacizumab plus

1

Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol 2002;29(suppl 16):15–18.

2

Folkman J. Tumor angiogenesis: Therapeutic implications. N Engl J Med 1971;285:1182–1186.

3

Kerbel R, Folkman J. Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2002;2:727–739.

4

Ferrara N. Vascular endothelial growth factor: Basic science and clinical progress. Endocr Rev 2004;25:581– 611.

5

Ferrara N. VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer 2002;2:795– 803.

6

Lenihan DJ. Tyrosine kinase inhibitors: Can promising new therapy associated with cardiac toxicity strengthen the concept of teamwork? J Clin Oncol 2008;26:5154 –5155.

7

Mourad JJ, des Guetz G, Debbabi H et al. Blood pressure rise following angiogenesis inhibition by bevacizumab. A crucial role for microcirculation. Ann Oncol 2008;19:927–934.

8

Gordon MS, Margolin K, Talpaz M et al. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol 2001;19:843– 850.

9

Czito BG, Bendell JC, Willett CG et al. Bevacizumab, oxaliplatin, and capecitabine with radiation therapy in rectal cancer: Phase I trial results. Int J Radiat Oncol Biol Phys 2007;68:472– 478.

10

Seiwert TY, Haraf DJ, Cohen EE et al. Phase I study of bevacizumab added to fluorouracil- and hydroxyurea-based concomitant chemoradiotherapy for poor-prognosis head and neck cancer. J Clin Oncol 2008;26: 1732–1741.

11

12

13

Margolin K, Gordon MS, Holmgren E et al. Phase Ib trial of intravenous recombinant humanized monoclonal antibody to vascular endothelial growth factor in combination with chemotherapy in patients with advanced cancer: Pharmacologic and long-term safety data. J Clin Oncol 2001;19:851– 856. Herbst RS, Johnson DH, Mininberg E et al. Phase I/II trial evaluating the anti-vascular endothelial growth factor monoclonal antibody bevacizumab in combination with the HER-1/epidermal growth factor receptor tyrosine kinase inhibitor erlotinib for patients with recurrent non-smallcell lung cancer. J Clin Oncol 2005;23:2544 –2555. Azad NS, Posadas EM, Kwitkowski VE et al. Combination targeted therapy with sorafenib and bevacizumab results in enhanced toxicity and antitumor activity. J Clin Oncol 2008;26:3709 –3714.

AUTHOR CONTRIBUTIONS Conception/Design: Apostolia Maria Tsimberidou Financial support: Apostolia Maria Tsimberidou Administrative support: Apostolia Maria Tsimberidou, Razelle Kurzrock Collection and/or assembly of data: Apostolia Maria Tsimberidou, Christos Vaklavas Data analysis and interpretation: Apostolia Maria Tsimberidou, Daniel Lenihan, Christos Vaklavas Manuscript writing: Apostolia Maria Tsimberidou, Daniel Lenihan, Christos Vaklavas Final approval of manuscript: Apostolia Maria Tsimberidou, Daniel Lenihan, Razelle Kurzrock, Christos Vaklavas


139

gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 2005;23:8033– 8040. 26

27

Ko AH, Dito E, Schillinger B et al. A phase II study evaluating bevacizumab in combination with fixed-dose rate gemcitabine and low-dose cisplatin for metastatic pancreatic cancer: Is an anti-VEGF strategy still applicable? Invest New Drugs 2008;26:463– 471. Lai A, Filka E, McGibbon B et al. Phase II pilot study of bevacizumab in combination with temozolomide and regional radiation therapy for upfront treatment of patients with newly diagnosed glioblastoma multiforme: Interim analysis of safety and tolerability. Int J Radiat Oncol Biol Phys 2008;71:1372–1380.

tion with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: Results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 2007;25:1539 – 1544. 43

Hurwitz HI, Fehrenbacher L, Hainsworth JD et al. Bevacizumab in combination with fluorouracil and leucovorin: An active regimen for first-line metastatic colorectal cancer. J Clin Oncol 2005;23:3502–3508.

44

Sandler A, Gray R, Perry MC et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355: 2542–2550.

45

Miller K, Wang M, Gralow J et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007;357: 2666 –2676.

46

Johnson DH, Fehrenbacher L, Novotny WF et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 2004;22:2184 –2191.

28

Lilenbaum R, Raez L, Tseng J et al. Efficacy and safety of oxaliplatin and gemcitabine with bevacizumab in advanced non-small cell lung cancer. J Thorac Oncol 2008;3:511–515.

29

Meyerhardt JA, Stuart K, Fuchs CS et al. Phase II study of FOLFOX, bevacizumab and erlotinib as first-line therapy for patients with metastatic colorectal cancer. Ann Oncol 2007;18:1185–1189.

30

Micha JP, Goldstein BH, Rettenmaier MA et al. A phase II study of outpatient first-line paclitaxel, carboplatin, and bevacizumab for advancedstage epithelial ovarian, peritoneal, and fallopian tube cancer. Int J Gynecol Cancer 2007;17:771–776.

47

Grothey A, Sugrue MM, Purdie DM et al. Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: Results from a large observational cohort study (BRiTE). J Clin Oncol 2008;26:5326 –5334.

31

Nimeiri HS, Oza AM, Morgan RJ et al. Efficacy and safety of bevacizumab plus erlotinib for patients with recurrent ovarian, primary peritoneal, and fallopian tube cancer: A trial of the Chicago, PMH, and California Phase II Consortia. Gynecol Oncol 2008;110:49 –55.

48

Miller KD, Chap LI, Holmes FA et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005;23:792– 799.

32

Ramaswamy B, Elias AD, Kelbick NT et al. Phase II trial of bevacizumab in combination with weekly docetaxel in metastatic breast cancer patients. Clin Cancer Res 2006;12:3124 –3129.

49

Scappaticci FA, Skillings JR, Holden SN et al. Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst 2007;99:1232–1239.

33

Shah MA, Ramanathan RK, Ilson DH et al. Multicenter phase II study of irinotecan, cisplatin, and bevacizumab in patients with metastatic gastric or gastroesophageal junction adenocarcinoma. J Clin Oncol 2006;24: 5201–5206.

50

Nalluri SR, Chu D, Keresztes R et al. Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: A metaanalysis. JAMA 2008;300:2277–2285.

51

34

Zhu AX, Blaszkowsky LS, Ryan DP et al. Phase II study of gemcitabine and oxaliplatin in combination with bevacizumab in patients with advanced hepatocellular carcinoma. J Clin Oncol 2006;24:1898 –1903.

Tammela T, Zarkada G, Wallgard E et al. Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature 2008;454: 656 – 660.

52

35

Gruenberger B, Tamandl D, Schueller J et al. Bevacizumab, capecitabine, and oxaliplatin as neoadjuvant therapy for patients with potentially curable metastatic colorectal cancer. J Clin Oncol 2008;26:1830 –1835.

Bergers G, Song S, Meyer-Morse N et al. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. The J Clin Invest 2003;111:1287–1295.

53

36

Vredenburgh JJ, Desjardins A, Herndon JE 2nd et al. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res 2007;13:1253–1259.

Faivre S, Delbaldo C, Vera K et al. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 2006;24:25–35.

54

37

Dellapasqua S, Bertolini F, Bagnardi V et al. Metronomic cyclophosphamide and capecitabine combined with bevacizumab in advanced breast cancer. J Clin Oncol 2008;26:4899 – 4905.

Fiedler W, Serve H, Döhner H et al. A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease. Blood 2005;105:986 –993.

38

Di Lorenzo G, Figg WD, Fossa SD et al. Combination of bevacizumab and docetaxel in docetaxel-pretreated hormone-refractory prostate cancer: A phase 2 study. Eur Urol 2008;54:1089 –1094.

55

Britten CD, Kabbinavar F, Hecht JR et al. A phase I and pharmacokinetic study of sunitinib administered daily for 2 weeks, followed by a 1-week off period. Cancer Chemother Pharmacol 2008;61:515–524.

39

Kabbinavar F, Hurwitz HI, Fehrenbacher L et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 2003;21:60 – 65.

56

Motzer RJ, Michaelson MD, Redman BG et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 2006;24:16 –24.

40

Yang JC, Haworth L, Sherry RM et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003;349:427– 434.

57

Motzer RJ, Rini BI, Bukowski RM et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA 2006;295:2516 –2524.

58

41

Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335–2342.

Burstein HJ, Elias AD, Rugo HS et al. Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 2008;26:1810 –1816.

42

Giantonio BJ, Catalano PJ, Meropol NJ et al. Bevacizumab in combina-

59

Saltz LB, Rosen LS, Marshall JL et al. Phase II trial of sunitinib in patients



140 with metastatic colorectal cancer after failure of standard therapy. J Clin Oncol 2007;25:4793– 4799.

afenib (BAY 43–9006) in combination with doxorubicin in patients with refractory solid tumors. Ann Oncol 2006;17:866 – 873.

60

Socinski MA, Novello S, Brahmer JR et al. Multicenter, phase II trial of sunitinib in previously treated, advanced non-small-cell lung cancer. J Clin Oncol 2008;26:650 – 656.

79

Duran I, Hotté SJ, Hirte H et al. Phase I targeted combination trial of sorafenib and erlotinib in patients with advanced solid tumors. Clin Cancer Res 2007;13:4849 – 4857.

61

Kulke MH, Lenz HJ, Meropol NJ et al. Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol 2008;26:3403–3410.

80

62

Rini BI, Michaelson MD, Rosenberg JE et al. Antitumor activity and biomarker analysis of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma. J Clin Oncol 2008;26:3743–3748.

Adjei AA, Molina JR, Mandrekar SJ et al. Phase I trial of sorafenib in combination with gefitinib in patients with refractory or recurrent nonsmall cell lung cancer. Clin Cancer Res 2007;13:2684 –2691.

81

Escudier B, Lassau N, Angevin E et al. Phase I trial of sorafenib in combination with IFN alpha-2a in patients with unresectable and/or metastatic renal cell carcinoma or malignant melanoma. Clin Cancer Res 2007;13: 1801–1809.

82

Flaherty KT, Schiller J, Schuchter LM et al. A phase I trial of the oral, multikinase inhibitor sorafenib in combination with carboplatin and paclitaxel. Clin Cancer Res 2008;14:4836 – 4842.

83

Akaza H, Tsukamoto T, Murai M et al. Phase II study to investigate the efficacy, safety, and pharmacokinetics of sorafenib in Japanese patients with advanced renal cell carcinoma. Jpn J Clin Oncol 2007;37:755–762.

63

Demetri GD, van Oosterom AT, Garrett CR et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: A randomised controlled trial. Lancet 2006;368:1329 – 1338.

64

Motzer RJ, Hutson TE, Tomczak P et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356:115–124.

65

Chu TF, Rupnick MA, Kerkela R et al. Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet 2007;370:2011–2019.

66

Khakoo AY, Halushka MK, Rame JE et al. Reversible cardiomyopathy caused by administration of interferon alpha. Nat Clin Pract Cardiovasc Med 2005;2:53–57.

84

Abou-Alfa GK, Schwartz L, Ricci S et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2006;24: 4293– 4300.

67

Rock EP, Goodman V, Jiang JX et al. Food and Drug Administration drug approval summary: Sunitinib malate for the treatment of gastrointestinal stromal tumor and advanced renal cell carcinoma. The Oncologist 2007; 12:107–113.

85

Elser C, Siu LL, Winquist E et al. Phase II trial of sorafenib in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or nasopharyngeal carcinoma. J Clin Oncol 2007;25:3766 –3773.

86

68

Khakoo AY, Kassiotis CM, Tannir N et al. Heart failure associated with sunitinib malate: A multitargeted receptor tyrosine kinase inhibitor. Cancer 2008;112:2500 –2508.

Chi KN, Ellard SL, Hotte SJ et al. A phase II study of sorafenib in patients with chemo-naive castration-resistant prostate cancer. Ann Oncol 2008; 19:746 –751.

87

69

Telli ML, Witteles RM, Fisher GA et al. Cardiotoxicity associated with the cancer therapeutic agent sunitinib malate. Ann Oncol 2008;19:1613– 1618.

Dahut WL, Scripture C, Posadas E et al. A phase II clinical trial of sorafenib in androgen-independent prostate cancer. Clin Cancer Res 2008; 14:209 –214.

88

70

Hood JD, Bednarski M, Frausto R et al. Tumor regression by targeted gene delivery to the neovasculature. Science 2002;296:2404 –2407.

71

Awada A, Hendlisz A, Gil T et al. Phase I safety and pharmacokinetics of BAY 43–9006 administered for 21 days on/7 days off in patients with advanced, refractory solid tumours. Br J Cancer 2005;92:1855–1861.

Steinbild S, Mross K, Frost A et al. A clinical phase II study with sorafenib in patients with progressive hormone-refractory prostate cancer: A study of the CESAR Central European Society for Anticancer Drug ResearchEWIV. Br J Cancer 2007;97:1480 –1485.

89

Gupta-Abramson V, Troxel AB, Nellore A et al. Phase II trial of sorafenib in advanced thyroid cancer. J Clin Oncol 2008;26:4714 – 4719.

90

Ratain MJ, Eisen T, Stadler WM et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 2006;24:2505–2512.

91

Eisen T, Ahmad T, Flaherty KT et al. Sorafenib in advanced melanoma: A phase II randomised discontinuation trial analysis. Br J Cancer 2006;95: 581–586.

72

Clark JW, Eder JP, Ryan D et al. Safety and pharmacokinetics of the dual action Raf kinase and vascular endothelial growth factor receptor inhibitor, BAY 43–9006, in patients with advanced, refractory solid tumors. Clin Cancer Res 2005;11:5472–5480.

73

Furuse J, Ishii H, Nakachi K et al. Phase I study of sorafenib in Japanese patients with hepatocellular carcinoma. Cancer Sci 2008;99:159 –165.

74

Minami H, Kawada K, Ebi H et al. Phase I and pharmacokinetic study of sorafenib, an oral multikinase inhibitor, in Japanese patients with advanced refractory solid tumors. Cancer Sci 2008;99:1492–1498.

92

Gollob JA, Rathmell WK, Richmond TM et al. Phase II trial of sorafenib plus interferon alfa-2b as first- or second-line therapy in patients with metastatic renal cell cancer. J Clin Oncol 2007;25:3288 –3295.

75

Moore M, Hirte HW, Siu L et al. Phase I study to determine the safety and pharmacokinetics of the novel Raf kinase and VEGFR inhibitor BAY 43– 9006, administered for 28 days on/7 days off in patients with advanced, refractory solid tumors. Ann Oncol 2005;16:1688 –1694.

93

Ryan CW, Goldman BH, Lara PN Jr et al. Sorafenib with interferon alfa-2b as first-line treatment of advanced renal carcinoma: A phase II study of the Southwest Oncology Group. J Clin Oncol 2007;25:3296 – 3301.

76

Strumberg D, Richly H, Hilger RA et al. Phase I clinical and pharmacokinetic study of the novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43–9006 in patients with advanced refractory solid tumors. J Clin Oncol 2005;23:965–972.

94

McDermott DF, Sosman JA, Gonzalez R et al. Double-blind randomized phase II study of the combination of sorafenib and dacarbazine in patients with advanced melanoma: A report from the 11715 Study Group. J Clin Oncol 2008;26:2178 –2185.

77

Siu LL, Awada A, Takimoto CH et al. Phase I trial of sorafenib and gemcitabine in advanced solid tumors with an expanded cohort in advanced pancreatic cancer. Clin Cancer Res 2006;12:144 –151.

95

Escudier B, Eisen T, Stadler WM et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356:125–134.

96

78

Richly H, Henning BF, Kupsch P et al. Results of a phase I trial of sor-

Llovet JM, Ricci S, Mazzaferro V et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378 –390.


141

97

Veronese ML, Mosenkis A, Flaherty KT et al. Mechanisms of hypertension associated with BAY 43–9006. J Clin Oncol 2006;24:1363–1369.

106 Force T, Krause DS, Van Etten RA. Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer 2007;7:332–344.

98

Schmidinger M, Zielinski CC, Vogl UM et al. Cardiac toxicity of sunitinib and sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 2008;26:5204 –5212.

107 Nachman RL, Rafii S. Platelets, petechiae, and preservation of the vascular wall. N Engl J Med 2008;359:1261–1270.

99

Kane RC, Farrell AT, Saber H et al. Sorafenib for the treatment of advanced renal cell carcinoma. Clin Cancer Res 2006;12:7271–7278.

108 Elice F, Rodeghiero F, Falanga A et al. Thrombosis associated with angiogenesis inhibitors. Best Pract Res Clin Haematol 2009;22:115–128.

100 Henry TD, Annex BH, McKendall GR et al. The VIVA trial: Vascular endothelial growth factor in Ischemia for Vascular Angiogenesis. Circulation 2003;107:1359 –1365.

109 Advani A, Kelly DJ, Advani SL et al. Role of VEGF in maintaining renal structure and function under normotensive and hypertensive conditions. Proc Natl Acad Sci U S A 2007;104:14448 –14453.

101 Noon JP, Walker BR, Webb DJ et al. Impaired microvascular dilatation and capillary rarefaction in young adults with a predisposition to high blood pressure. J Clin Invest 1997;99:1873–1879.

110 Schneider BP, Wang M, Radovich M et al. Association of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 genetic polymorphisms with outcome in a trial of paclitaxel compared with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 2100. J Clin Oncol 2008;26:4672– 4678.

102 Felmeden DC, Spencer CG, Belgore FM et al. Endothelial damage and angiogenesis in hypertensive patients: Relationship to cardiovascular risk factors and risk factor management. Am J Hypertens 2003;16:11–20. 103 Friehs I, Barillas R, Vasilyev NV et al. Vascular endothelial growth factor prevents apoptosis and preserves contractile function in hypertrophied infant heart. Circulation 2006;114(1 suppl):I290 –I295. 104 Giordano FJ, Gerber HP, Williams SP et al. A cardiac myocyte vascular endothelial growth factor paracrine pathway is required to maintain cardiac function. Proc Natl Acad Sci U S A 2001;98:5780 –5785. 105 Zentilin L, Puligadda U, Lionetti V et al. Cardiomyocyte VEGFR-1 activation by VEGF-B induces compensatory hypertrophy and preserves cardiac function after myocardial infarction. FASEB J 2009 Dec 17 [Epub ahead of print].


111 Khakoo AY, Sidman RL, Pasqualini R et al. Does the renin-angiotensin system participate in regulation of human vasculogenesis and angiogenesis? Cancer Res 2008;68:9112–9115. 112 Thaker PH, Lutgendorf SK, Sood AK. The neuroendocrine impact of chronic stress on cancer. Cell Cycle 2007;6:430 – 433. 113 Eremina V, Jefferson JA, Kowalewska J et al. VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med 2008;358:1129 –1136. 114 Glynn RJ, Danielson E, Fonseca FA et al. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Engl J Med 2009; 360:1851–1861.