Vascular Toxicities of Novel Cancer Therapies
Introduction
Numerous types of cancer treatments, ranging from immunotherapy, traditional chemotherapy (e.g., doxorubicin), and targeted therapy (e.g., tyrosine kinase inhibitors [TKIs]) are associated with vascular toxicities. As cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in patients with and without cancer, there is an urgent need to better understand the mechanisms and manifestations of vascular side effects to improve the care of cancer patients. In this brief review, we will summarize the common vascular toxicities associated with cancer therapies and provide a broad overview on their management.
Systemic Hypertension
Systemic hypertension is a common vascular toxicity due to vascular endothelial growth factor (VEGF) signaling pathway inhibition and is also a clinical marker of therapy efficacy.1 VEGF binds to VEGF receptors (VEGFR), promoting angiogenesis.2,3 VEGF signaling pathway inhibitors (VSPi) take advantage of tumor cells' dependence on blood supply by inhibiting VEGF signaling through various mechanisms of action: VEGF antibodies (e.g., bevacizumab), VEGFR antibodies (e.g., ramucirumab), and VEGFR TKIs (e.g., sorafenib, sunitinib) (Table 1).4 VSPi-associated hypertension is an "on-target" effect, affecting up to 90% of patients with newer generation VSPi (e.g., lenvatinib, lucitanib, axitinib).5,6 Life-threatening hypertensive crises, such as posterior reversible encephalopathy, are rare.7 Patients with pre-existing hypertension, advanced age (>60 years), tobacco use, hyperlipidemia, and obesity are at highest risk for VSPi associated hypertension.8,9 Mechanisms have been reviewed previously4,10 and are summarized in Table 2 below.
Table 1: VEGF Signaling Pathway (VSP) Inhibitors
Target | Name | Mechanisms | Cardiovascular Toxicities | Cancer(s) |
VEGF-A | Bevacizumab (Avastin) | Monoclonal antibody (mAb); humanized anti-VEGF antibody | Hypertension Arterial and venous thromboembolism Reversible cardiomyopathy Congestive heart failure Cardiac hypertrophy Myocardial infarction Cerebral ischemia Bleeding Proteinuria |
Metastatic colorectal cancer Advanced non-squamous non-small cell lung cancer Metastatic renal cell carcinoma Recurrent glioblastoma Advanced cervical cancer |
VEGFR2 | Ramucirumab | mAb; binds to VEGFR-2 and blocks binding of VEGFR ligands, such as VEGF-A, VEGF-C, and VEGF-D | Hypertension Reversible cardiomyopathy Arterial and venous thromboembolism Bleeding Peripheral edema Proteinuria |
Advanced gastric or GE junction adenocarcinoma Metastatic NSCLC Metastatic colorectal cancer Advanced hepatocellular carcinoma |
VEGFR1 | Icrucumab | mAb; binds to VEGFR-1 and inhibits downstream signaling | Peripheral edema Anemia No cardiotoxicity or hypertension identified |
Under clinical investigation for advanced solid cancers (e.g., small cell lung cancer, colorectal cancer) |
VEGF | Ziv-aflibercept | VEGF-trap; peptide-antibody fusion protein that binds to circulating VEGF members (VEGF-A, VEGF-B) and placental growth factor | Hypertension Arterial and venous thromboembolism Cardiomyopathy Bleeding Proteinuria |
Metastatic colorectal cancer |
Multi-target Tyrosine Kinase Inhibitors (TKI) | Axitinib | VEGFR1, 2, 3; PDGFR; c-KIT | Hypertension Cardiomyopathy Arterial and venous thromboembolism Bleeding Proteinuria |
Advanced RCC, advanced neuroendocrine tumors of non-pancreatic origin |
Cabozantinib | VEGFR1, 2, 3, RET, FLT3; c-MET, AXL | Hypertension Cardiomyopathy Arterial and venous thromboembolism Bleeding Proteinuria |
Advanced RCC Metastatic medullary thyroid cancer Hepatocellular cancer |
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Lenvatinib | VEGFR 1, 2, 3; FGFR 1-4, PDGFRA, RET | Hypertension Cardiomyopathy Arterial and venous thromboembolism Bleeding QT prolongation Proteinuria |
Iodine-131-refractory thyroid cancer | |
Cediranib | VEGFR1 2, 3; c-KIT; PDGFR | Hypertension Arterial and venous thromboembolism QT prolongation Proteinuria |
Advanced RCC, GIST, soft tissue sarcoma, HCC, advanced non-small cell lung cancer, advanced colorectal cancer, mesothelioma, breast cancer, ovarian cancer , GBM | |
Nintedanib | PDGFR, FGFR, VEGFR-1, 2, 3; FLT3 | Hypertension Arterial and venous thromboembolism Myocardial infarction Bleeding Proteinuria |
Locally advanced, metastatic, or locally recurring non-small cell lung cancer (in combination with docetaxel); interstitial lung disease | |
Pazopanib | VEGFR 1, 2, 3, PDGFR, FGFR, c-KIT, Flt-3, RET | Hypertension Cardiomyopathy Thromboembolism QT prolongation Torsades de pointes Proteinuria |
Metastatic medullary thyroid cancer Advanced renal cell carcinoma Advanced soft tissue sarcomas |
|
Sunitinib | VEGFR 1, 2, 3, PDGFR-A and -B, c-KIT, RET, CD114, CD135 | Hypertension Reversible cardiomyopathy Arterial and venous thromboembolism Cardiac ischemia QT prolongation Proteinuria |
Advanced RCC, Progressive well-differentiated pancreatic neuroendocrine tumors, GIST | |
Sorafenib | RAF kinase, VEGFR 1, 2, 3, PDGFR-B, RET, c-KIT, FLT3 | Hypertension Reversible cardiomyopathy Cardiac ischemia Arterial and venous thromboembolism Bleeding QT prolongation Proteinuria |
Advanced RCC, advanced unresectable HCC, GIST, angiosarcoma, advanced thyroid carcinoma refractory to radioactive iodine treatment | |
Apatinib | VEGFR2, c-KIT, c-SRC | Hypertension Bleeding Left ventricular dysfunction Proteinuria |
Metastatic gastric carcinoma, metastatic breast cancer; advanced HCC, refractory metastatic colorectal cancer | |
Lucitanib | VEGFR1, 2, 3, PGFRA/B, FGFR1 and 2 | Hypertension QT prolongation Proteinuria |
Advanced solid tumors (in clinical trials) | |
Regorafenib | VEGFR 1, 2,3; TIE-2, RET, PDGFB, basic FGF-1, c-KIT, RAF-1, BRAF | Hypertension Thrombosis Heart failure Bleeding Proteinuria |
Advanced HCC, Advanced GIST, metastatic colorectal cancer | |
Vandetanib | VEGFR-2, 3, EGFR, PDGFR, RET | Hypertension Cardiomyopathy QT prolongation |
Advanced RCC, medullary thyroid cancer, NSCLC | |
Vatalanib | VEGFR1, 2, 3; PDGFR, c-KIT | Hypertension Heart failure Venous thromboembolism |
Advanced solid tumors | |
Surufatinib |
VEGFR1, 2, 3; FGFR1, CSF1R | Hypertension Proteinuria Hypertriglyceridemia |
Advanced solid tumors; advanced medullary thyroid cancer | |
Famitinib | VEGFR2 and 3, PDGFR, c-KIT, FGFR | Hypertension | Advanced genitourinary and gynecologic cancers | |
Ponatinib | BCR-ABL, FGFR, VEGFR1, 2, 3, PDGFR, c-KIT, RET, FLT3 | Hypertension Arterial and venous thromboembolism Cardiac ischemia Atrial fibrillation Proteinuria |
Resistant Philadelphia chromosome-positive chronic myelogenous leukemia and acute lymphocytic leukemia |
Prior to initiation of VSPi, baseline blood pressures should be optimized (goal <130/80 mmHg) with lifestyle modifications and anti-hypertensive medications. During treatment with VSPi, blood pressures should be closely monitored, and hypertension should be treated with first-line medications according to the Joint National Committee (JNC 8) guidelines (Table 2).
Table 2: Proposed Mechanisms and Management of Common Vascular Toxicities
Thromboembolism | CAD/MI | PAD | Hypertension | PAH | Arterial Vasospasm | |||
Proposed Mechanism(s) |
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Management* | Step 1 |
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Screening |
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Diagnosis |
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Treatment |
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5-FU, 5-fluorouracil; ABI, ankle-brachial index; ACEi, angiotensin-converting enzyme inhibitors; ACS, acute coronary syndrome; ARB, angiotensin receptor blockers; ASCVD, atherosclerotic cardiovascular disease; CACs, coronary artery calcium score; CAD, coronary artery disease; CCB, calcium channel blockers; cCTA, coronary CT angiography; CHF, congestive heart failure; CPET, cardiopulmonary exercise testing; CVD, cardiovascular disease; ERAs, endothelin-receptor antagonists; HTN, hypertension; ICIs, immune checkpoint inhibitors; LE, lower extremity; MI, myocardial infarction; PAD, peripheral artery disease; PAH, pulmonary arterial hypertension; PCI, percutaneous coronary intervention; PDE-5, phosphodiesterase-5; PND, paroxysmal nocturnal dyspnea; RV, right ventricle; RVH, right ventricular hypertrophy; TKIs, tyrosine kinase inhibitors; UE, upper extremity; VEGF, vascular endothelial growth factor; WMA, wall motion abnormalities
Venous and Arterial Thromboembolism
Thromboembolism is prevalent in cancer patients and is associated with high rates of morbidity and mortality.11 Cancer treatment can further increase the incidence of venous- (VTE) and arterial thromboembolism (ATE), including thrombotic events such as myocardial ischemia/infarction (MI) (Figure 1). The mechanisms of increased thrombosis due to cancer therapies are proposed to include endothelial activation, endothelial cytotoxicity, platelet activation, and reduced anticoagulant activity. Here, we will focus on targeted therapies and immunotherapies.
Though TKIs result in potent antineoplastic effects by blocking downstream signaling pathways of their targets (e.g., VEGFR, platelet derived growth factor receptor [PDGFR]), their use is associated with an increased risk of thromboembolism (Table 1). For example, sunitinib and sorafenib are associated with a three-fold increase in the risk of ATE.12 Additional VEGFR-TKIs (e.g., pazopanib, vandetanib, axitinib, etc.) are associated with an increased risk of ATE and thrombosis (1.4% vs. 0.5%, OR = 2.26), with MI being the most common.13 The proposed mechanisms include endothelial cell dysfunction and altered vasodilator homeostasis.4 Bevacizumab also increases the risk of both VTE and ATE.14 Indeed, bevacizumab almost doubles the risk of ATE in cancer patients, in part due to increased platelet activation.15-18
BCR-ABL TKIs are currently the standard of care for chronic myeloid leukemia (CML). Second-generation TKIs (nilotinib, dasatinib, ponatinib) have a greater binding affinity for BCR-ABL1 and are more efficacious compared to first-generation TKI (imatinib).19-21 Notably, patients on newer generation TKIs are three times more likely to develop ATE compared to those treated with imatinib.22,23 Preclinical studies suggest that platelet activation is the primary mechanism of ponatinib-associated ATE.24,25
Immune checkpoint inhibitors (ICIs) are increasingly being used as first-line cancer therapies.26,27 ICIs are monoclonal antibodies that impair tumor escape mechanisms by targeting immune checkpoints, such as CTLA-4, PD-1, and PD-L1, among others (e.g., LAG3). Though ATE and VTE have been reported in patients taking ICI, incidence rates are unclear due to lack of systematic toxicity monitoring.28-30 A recent single center retrospective study reported a cumulative incidence of 12.9% (VTE) and 0.6% (ATE) in patients treated with ICIs but a control group was lacking.31 Proposed mechanisms include vasculitis and vascular thrombotic events.32
The management of thromboembolism in cancer patients should be individualized based on bleeding and clotting risks. Though anticoagulation is the most common treatment, fibrinolysis, antiplatelet therapy, and mechanical thrombectomy can be considered on an individualized basis.33 The most recent ASCO (American Society of Clinical Oncology) guidelines do not recommend routine thromboprophylaxis for all cancer patients, though can be considered in high-risk patients (Table 2).34
Atherosclerosis and Peripheral Artery Disease
Peripheral artery disease (PAD) is characterized by progressive atherosclerosis and stenosis of large and medium-sized arteries. PAD commonly affects the lower extremities, resulting in claudication.35 Various cancer therapies have been shown to accelerate atherosclerosis and PAD, especially in patients with underlying CVD risk factors (Figure 1).
PAD is associated with second-generation BCR-ABL TKIs (e.g. nilotinib, ponatinib). Notably, imatinib has a favorable CV side effect profile and may even reduce the risk of PAD.36 Compared to imatinib, nilotinib use is associated with increased risk of pathological ankle-brachial index (ABI) values (RR = 10.3; 95% CI 2.3-61.5).37 Cases of nilotinib-associated PAD can be severe and rapidly progressive, sometimes requiring angioplasty or surgical revascularization.38-40 Ponatinib is also associated with advanced atherosclerosis, including acute MI.41 Recent meta-analyses have confirmed the increased risk of arterial vascular events (e.g. PAD, MI, CVD) with both nilotinib and ponatinib.42,43 Potential mechanisms are summarized in Table 2.
Though clinical reports of accelerated atherosclerosis or PAD in ICIs are limited, pre-clinical studies have demonstrated that genetic deficiency of PD-L1, PD-L2, or PD1 increase inflammatory cell infiltration in atherosclerotic plaques, suggesting a potential link between ICIs and atherosclerosis.44,45 It is thought that ICIs inhibit critical negative regulators of atherosclerosis.32 A recent single-center study showed that patients treated with ICIs are 3.3 times more likely to have an atherosclerotic CV event, defined as MI, coronary revascularization, and ischemic stroke, compared to matched controls over years.46
Management of atherosclerotic disease in cancer patients should be individualized based on risk factors and baseline CV disease. Patients with high CVD risk profiles are more vulnerable to vascular toxicities with TKIs compared to those with low risk profiles.47 Risk factors (e.g., obesity, smoking, diabetes, hypertension, hypercholesterolemia) should be assessed and optimized in patients prescribed BCR-ABL inhibitors. CV and metabolic parameters, including ABI measurements, should be monitored regularly. In patients taking nilotinib or ponatinib with high-grade PAD (i.e., severe claudication plus abnormal ABI or imaging), the TKI should be replaced with another if possible.48
Pulmonary Hypertension
Pulmonary hypertension (PH) is defined by a mean pulmonary artery pressure (mPAP) >20mmHg measured during right heart catheterization (RHC).49 Group 1 PH or pulmonary arterial hypertension (PAH) includes drug-induced, idiopathic, and toxin-induced, and results from uncontrolled growth of endothelial and smooth-muscle cells in the pulmonary vasculature.50,51 Untreated PH can lead to increased pulmonary vascular resistance (PVR), RV hypertrophy and remodeling, culminating in RV failure.
Dasatinib (second-generation BCL-ABL TKI) has been associated with reversible PAH.52-56 Though the incidence of dasatinib-associated PAH was initially estimated to be 0.45%,57 recent studies report an incidence rate of up to 5%.58-60 However, this is likely higher due to under-diagnosis of subclinical PH, as well as recently updated diagnostic criteria (i.e.., mPAP >20mmHg rather than ≥25mmHg). Though cessation of dasatinib typically decreases mPAP, long-term follow up data showed that one-third of patients had persistently elevated mPAP and PVR.61 The proposed mechanisms of dasatinib-induced PAH are summarized in Table 2.
Management of PH in cancer patients is based on guidelines in the general population.62,63 Prior to initiation of dasatinib, patients should be evaluated for signs of underlying cardiopulmonary disease. Patients who develop dyspnea and symptoms of RV dysfunction (e.g., peripheral edema), should be evaluated with electrocardiogram (ECG) and transthoracic echocardiogram (TTE). If PAH is suspected, RHC should be considered. Once PH is confirmed, the culprit drug should be discontinued, and pulmonary vasodilators initiated.
Coronary Artery Vasospasm
Coronary artery vasospasm typically presents with angina, troponin elevation, and ischemic ECG changes. Traditional chemotherapy agents, specifically 5-fluorouracil (5-FU) and capecitabine (prodrug of 5-FU), have the highest risk of vasospasm.64,65 Patients with underlying coronary artery disease or pre-existing endothelial dysfunction are at higher risk of coronary vasospasm.66 Pharmacogenetic variants in DPYD (dihydropyrimidine dehydrogenase) and TYMS (thymidylate synthase) are associated with an increased risk of high grade toxicity.67 Cases of coronary vasospasm have also been reported with other therapies (e.g., paclitaxel, bevacizumab, sorafenib, radiotherapy) (Figure 1). Management recommendations are summarized in Table 2.
Figure 1: Common Vascular Toxicities Associated with Cancer Therapies
Figure created with biorender.com. Courtesy of Song EJ, Baik AH.
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Clinical Topics: Anticoagulation Management, Cardiac Surgery, Cardio-Oncology, Cardiovascular Care Team, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Stable Ischemic Heart Disease, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Anticoagulation Management and Venothromboembolism, Aortic Surgery, Cardiac Surgery and Heart Failure, Cardiac Surgery and SIHD, Homozygous Familial Hypercholesterolemia, Novel Agents, Statins, Heart Failure and Cardiac Biomarkers, Pulmonary Hypertension, Interventions and Coronary Artery Disease, Interventions and Vascular Medicine, Hypertension, Smoking, Chronic Angina
Keywords: Dasatinib, Ankle Brachial Index, Angioplasty, Antihypertensive Agents, Anticoagulants, Atherosclerosis, Axitinib, B7-H1 Antigen, Bevacizumab, Blood Pressure, Brain Diseases, Brain Ischemia, Cardiac Catheterization, Capecitabine, Cardiovascular Diseases, Classification, Constriction, Pathologic, Control Groups, Coronary Artery Disease, Coronary Vasospasm, CTLA-4 Antigen, Diabetes Mellitus, Dihydrouracil Dehydrogenase (NADP), Doxorubicin, Dyspnea, Rabeprazole, Edema, Electrocardiography, Endothelial Cells, Fibrinolysis, Follow-Up Studies, Goals, Homeostasis, Hypercholesterolemia, Hyperlipidemias, Hypertension, Hypertension, Pulmonary, Hypertrophy, Imatinib Mesylate, Immune Checkpoint Inhibitors, Immune Checkpoint Inhibitors, Immunotherapy, Infarction, Ischemic Stroke, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Life Style, Lower Extremity, Medical Oncology, Muscle Cells, Myocardial Ischemia, Neoplasms, Obesity, Paclitaxel, Peripheral Arterial Disease, Pharmacogenomic Variants, Plaque, Atherosclerotic, Platelet Activation, Platelet Aggregation Inhibitors, Prodrugs, Programmed Cell Death 1 Receptor, Protein Kinase Inhibitors, Pulmonary Arterial Hypertension, Pulmonary Artery, Receptors, Platelet-Derived Growth Factor, Receptors, Vascular Endothelial Growth Factor, Retrospective Studies, Risk Factors, Signal Transduction, Smoking, Sorafenib, Standard of Care, Stroke, Sunitinib, Thrombectomy, Thrombosis, Thymidylate Synthase, Tobacco Use, Troponin, Tumor Escape, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor A, Vascular Resistance, Vasculitis, Vasodilator Agents, Venous Thromboembolism
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