Table 2.

Summary of Main Vascular Toxicities Associated With Targeted Therapies and Proposed Mechanisms for Toxicities

Cancer Therapy	Proposed Mechanisms of Vascular Toxicity	Vascular Toxicities*
Antibody-related targeted therapies: VEGF-A monoclonal antibody (bevacizumab), VEGF-R2 monoclonal antibody (ramucirumab), VEGF-R1/R2 fused to Fc portion of IgG1 (aflibercept)	Reduction of PI3K-Akt, PLCγ-PKC/IP3, and Erk-MAPK signaling pathway activity in endothelial cells with reduction in eNOS activity, NO production, endothelial function, and cell survival and proliferation (capillary rarefaction) Increase in mitochondrial oxidative stress and eNOS uncoupling, reducing NO bioavailability	Cerebrovascular events Myocardial ischemia/MI Proteinuria Renal thrombotic microangiopathy Reversible posterior leukoencephalopathy syndrome Systemic hypertension Venous thromboembolic disease
Tyrosine kinase–related targeted therapies: primarily VEGF-R directed  Sorafenib  Sunitinib  Pazopanib  Axitinib  Regorafenib  Cabozantinib  Vandetanib  Lenvatinib	Reduction of PI3K-Akt, PLCγ-PKC/IP3, and Erk-MAPK signaling pathway activity in endothelial cells with reduction in eNOS activity, NO production, endothelial function, and cell survival and proliferation (capillary rarefication) Increase in mitochondrial oxidative stress and eNOS uncoupling, reducing NO bioavailability Increase in endothelin-1 production Rightward shift of the renal pressure–natriuresis curve, impaired sodium excretion, fluid retention, and salt-dependent hypertension Inhibition of PDGFβ-R signaling and pericyte function and survival with reduced VEGF and Ang-1 production and reduced VEGF-R and Tie-2 signaling activity in endothelial cells	Cerebrovascular events Myocardial ischemia/MI Proteinuria Renal thrombotic microangiopathy Systemic hypertension Venous thromboembolic disease Reversible posterior leukoencephalopathy syndrome
Tyrosine kinase-related targeted therapies: primarily ABL directed  Nilotinib  Ponatinib  Dasatinib	Reduction in endothelial cell c-Abl signaling and cell survival Reduction in VEGF-R2 signaling with reduction in endothelial function, survival, and proliferation	Cerebrovascular events Myocardial ischemia/MI Pulmonary hypertension (especially dasatinib) Systemic hypertension (especially ponatinib) Venous thromboembolic disease
Proteasome inhibitors (bortezomib, carfilzomib)	Induction of vascular oxidative stress Endothelial dysfunction and injury Inhibition of endothelial cell proliferation	Cerebrovascular events Myocardial ischemia/MI Systemic and pulmonary hypertension Venous thromboembolic disease
Immunomodulatory agents (thalidomide, lenalidomide)	Inhibition of endothelial cell migration Induction of homeostatic imbalance	Cerebrovascular events Myocardial ischemia/MI Systemic hypertension Venous thromboembolic disease
Immune checkpoint inhibitors: ipilimumab (CTLA-4), nivolumab (PD-1), permbrolizumab (PD-1), atezolizumab (PD-L1), avelumabn (PD-L1), durvalumab (PD-L1)	Activation of immune cells (T cells)	Myocarditis (vasculo-mediated) Vasculitis

ABL indicates Abelson murine leukemia viral oncogene homolog; Ang-1, angiopoietin 1; CTLA-4, cytotoxic T lymphocyte–associated protein 4; eNOS, endothelial nitric oxide synthase; Erk, extracellular signal–regulated kinase; Ig, immunoglobulin; IP3, inositol trisphosphate; MAPK, mitogen-activated protein kinase; MI, myocardial infarction; NO, nitric oxide; PDGFβ-R, platelet-derived growth factor-β receptor; PD-1, programmed cell death protein 1; PD-L1, programmed death ligand 1; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; PKC, protein kinase C; PLCγ, phosphoinositide phospholipase Cγ; Tie-2, tyrosine kinase with Ig and endothelial growth factor homology domains type 2; VEGF, vascular endothelial growth factor; and VEGF-R, vascular endothelial growth factor receptor.

^*Vascular toxicities are presented in alphabetical order. Order does not reflect prevalence of respective toxicities.