In many cases, old and new cancer therapies improve survival but may come at the expense of early and delayed cardiovascular complications. Although cardiomyopathies associated with cancer therapies such as anthracyclines or trastuzumab are well described, therapy-related vascular complications including systemic hypertension, myocardial ischemia, arterial and venous thrombosis, and pulmonary hypertension are often underappreciated. This review highlights the vascular complications and mechanisms of toxicity of new and older cancer therapies as well as potential strategies for prevention and treatment of vasculopathies. The vascular complications of some of the commonly used cancer therapies are summarized in Table 1.

Table 1. Vascular Complications Associated With Old and New Cancer Therapy^1,9,15,17,25

Cancer Therapy Agent	Systemic Hypertension	Cardiac Ischemia	Thromboembolism
Alkylating Agents Cisplatin Cyclophosphamide Ifosfamide	+ - -	+ - -	+ + +
Angiogenesis Inhibitors Lenalidomide Thalidomide Pomalidomide	+ - +	+ - -	+ + +
Antimetabolites 5-Fluorouracil Capecitabine	- -	+ +	+ +
Microtubule-Targeting Agents Docetaxel Paclitaxel	+ -	+ +	+ -
Monoclonal Antibodies Bevacizumab Rituximab Trastuzumab	+ + +	+ + -	+ + +
mTOR Inhibitors Everolimus Temsirolimus	+ +	- +	+ +
Proteasome Inhibitors Bortezomib Carfilzomib	+ +	- -	- -
Small Molecule Tyrosine Kinase Inhibitors Axitinib Dasatinib Imatinib Nilotinib Pazopanib Ponatinib Sorafenib Sunitinib Ziv-aflibercept	+ + - + + + + + +	+ + + + + + + + -	+ + + + + + + + +

Radiation-Induced Vasculopathy

Incidence and Mechanism

Mediastinal radiation therapy, an effective treatment for many types of cancers, carries an increased risk of cardiovascular complications in the decades following the initial treatment. Premature coronary artery disease (CAD) has been reported as early as 1 year and up to 30 years after treatment with a cumulative incidence for cardiac ischemia ranging from 1 to 13%.¹ The prevalence of asymptomatic severe CAD is estimated to be 3.1%.² In a case-control study of 2,168 women treated with radiotherapy for breast cancer, the risk of major coronary events increased linearly by 7.4% per Gy of radiation with no obvious lower threshold.³ The cardiovascular toxicity of radiation therapy is usually limited to structures in the radiation portal. Premature CAD usually involves the ostium or proximal coronary arteries and may be due to endothelial injury with subsequent changes typical of atherosclerosis. Histologically, the fibrosis of the arterial wall is diffuse, and there is little lipid deposition. Furthermore, endothelial dysfunction of the microvasculature leads to thrombosis and small vessel disease.⁴

Some of the risk factors for developing premature CAD include younger age at time of irradiation, mediastinal radiation dose ≥30-35 Gy, anthracycline use, and presence of CAD risk factors.^4,5 Modern radiotherapy techniques may lead to a lower rate or delayed radiation-induced heart disease.⁴

Carotid artery stenosis and subsequent stroke and transient ischemic attacks are also potential complications of radiation therapy involving the head and neck.⁶ In a cohort study of 1,387 childhood cancer survivors treated with mantle radiation for Hodgkin lymphoma, the relative risk of stroke was 5.6 (95% confidence interval, 2.59-12.25) with a median time to presentation of 17.5 years.⁷ Carotid artery lesions secondary to radiotherapy are more extensive and often involve longer segments of the artery than traditional atherosclerotic carotid disease.⁸

Management of radiation-induced vasculopathy includes vigilant risk factor modification, follow-up for detection of premature carotid artery stenosis and CAD, and percutaneous or surgical intervention when necessary. Coronary artery bypass grafting can be challenging in these patients given heavily calcified or friable internal mammary arteries.⁸

Chemotherapy-Induced Vasculopathy

Systemic Hypertension: Incidence and Mechanism

Systemic hypertension is a potential complication of certain cancer therapies, including vascular endothelial growth factor (VEGF) signaling pathway inhibitors, alkylating agents, taxanes, proteasome inhibitors, pyrimidine analogs, and vinca alkaloids.

The VEGF signaling pathway is critical to angiogenesis and can be inhibited by monoclonal antibodies and small molecule tyrosine kinase inhibitors directed at VEGF and its receptor, respectively. 9 Bevacizumab is a monoclonal antibody that is associated with systemic hypertension in up to 23.6% of patients overall.¹⁰ The incidence of overall hypertension for the small molecule tyrosine kinase inhibitors such as sunitinib, sorafenib, pazopanib, axitinib, and vandetanib ranges between 21.6 and 40.1%.⁹ Whereas some retrospective analyses have postulated that VEGF signaling pathway inhibitor-induced hypertension might correlate with anti-tumor response, this has yet to be validated in large prospective studies.¹¹ Although not well understood, an imbalance between vasoconstrictors and vasodilators, apoptosis of endothelial cells, decreased density and dilatory response of capillary beds (i.e., capillary rarefaction), and renal glomerular dysfunction could be potential mechanisms.¹²

Cisplatin, an alkylating agent, has also been associated with the development of systemic hypertension in up to 25-39% of small cohorts of testicular cancer survivors observed as late as 10-20 years after exposure.^13,14 Presence of microalbuminuria in patients with elevated blood pressure has been suggestive of possible endothelial damage as a possible mechanism of hypertension.¹³ Vinca alkaloids, rituximab, and interferon alpha have all been implicated to cause systemic hypertension to varying degrees.¹⁵

Management of the chemotherapy-related hypertension is vigilant blood pressure monitoring and aggressive treatment of hypertension during cancer therapy.⁵ In the case of VEGF signaling pathway inhibitors, hypertension is likely a marker of their efficacy, thus making discontinuation of the offending agent controversial. Chemotherapy-induced hypertension appears to resolve with discontinuation of the culpable agent and responds to antihypertensives; angiotensin-converting enzyme inhibitors, beta blockers, calcium channels blockers, and diuretics are commonly recommended.^5,16

Ischemic Heart Disease: Incidence and Mechanism

Various classes of chemotherapeutic agents can be associated with cardiac ischemia. Fluorouracil (5-FU) and its prodrug, capecitabine, both antimetabolites, can be associated with asymptomatic ST-segment depression, elevated cardiac enzymes, cardiac ischemia, CAD, and myocardial infarction.¹⁵ The incidence of cardiac ischemia associated with 5-FU and capecitabine is 3-7.6 and 3-9%, respectively, and usually occur within a few days of drug administration.^15,17 Multiple mechanisms for ischemia due to 5-FU have been implicated, including arterial vasoconstriction, endothelial injury and platelet aggregation, increased endothelin-1 levels, and alterations in red blood cell structure and function.¹⁸ Potential risk factors for 5-FU-related cardiotoxicity include concomitant radiation and chemotherapy (e.g., cisplatin), continuous infusions, doses over 800 mg/m², and prior history of CAD.¹⁸

Cardiac ischemia and myocardial infarction with the microtubule-targeting drug paclitaxel were observed in 5% of patients during and up to 14 days after drug administration.¹⁷ Cisplatin is associated with early and delayed myocardial ischemia and infarction up to 20 years after cancer remission in men with testicular tumors.¹³ Erlotinib, sorafenib, and bevacizumab are also associated with ischemia with incidences of approximately 2.3, 3, and <2%, respectively.^1,17

Data guiding the management of ischemic events related to chemotherapy are scarce, thus a collaborative approach is recommended, and established cardiovascular guidelines should be followed. Discontinuation of the responsible agent can lead to resolution of symptoms. Due to the potential for recurrence of ischemia, attempts should be made to use an alternative chemotherapeutic agent. However, in cases in which the offending agent must be continued, it remains unclear whether preventive antianginal therapy could be effective.⁵

Arterial and Venous Thromboembolism: Incidence and Mechanism

Arterial and venous thromboembolic events represent an important toxicity associated with certain chemotherapeutic agents. Bevacizumab is associated with the development of arterial thrombotic events in 3.3% of patients.¹⁰ The risk appears to be greatest in older patients, diabetics, and those with a history of arterial thrombotic events and may be due to endothelial dysfunction.¹⁹ Axitinib, pazopanib, sorafenib, and sunitinib are associated with a reported arterial thrombotic event incidence of <2%,^20,21 and the mechanism may involve endothelial cell dysfunction, defects in the endothelial layer, and altered bioavailability of important vasodilators with antiplatelet effects.⁹ Second and third generation BCR-ABL tyrosine kinase inhibitors, particularly nilotinib and ponatinib, are associated with potentially severe peripheral arterial occlusive disease and hence warrant vascular risk factor assessment prior to drug initiation.^9,22

Due to the multifactorial etiology of venous thromboembolism in patients with cancer (including the hypercoagulable state of malignancy), presence of indwelling catheters, and cancer therapies, the true incidence of chemotherapy-associated venous thromboembolism is difficult to define. Thalidomide is most commonly associated with venous thromboembolism; however, lenalidomide (a thalidomide analog), 5-FU, cisplatin, newer generation BCR-ABL kinase inhibitors, and the multi-targeted tyrosine kinase inhibitors may also be related to venous thromboembolism.^23-25

Management strategies include preventative measures such as aspirin for low-risk patients and full-dose anticoagulation in their high-risk counterparts.¹⁷

Pulmonary Hypertension: Incidence and Mechanism

Pulmonary hypertension is a rare complication of cancer therapy. Case reports and registry data of pulmonary arterial hypertension associated with dasatinib, a second-generation multi-targeted tyrosine kinase inhibitor, have led to published warnings about this rare complication.^23,26 The product labeling advises permanent discontinuation of dasatinib if pulmonary arterial hypertension is confirmed.²⁷ Pulmonary arterial hypertension has also been attributed to the proteasome inhibitors carfilzomib and bortezomib.^28,29 Cases of pulmonary veno-occlusive disease associated with cyclophosphamide, mitomycin, cisplatin, and bone marrow transplantation have also been identified.³⁰

Conclusion

Systemic hypertension, ischemic heart disease, arterial and venous thromboembolism, and pulmonary hypertension are potential complications of old and new cancer therapies that deserve recognition. Currently, the cardio-oncology literature is lacking the large, robust, randomized trials with the clearly defined endpoints for which cardiology is renowned. The recommended approach to this patient population is a collaborative approach with aggressive risk factor modification, early and long-term follow-up of vascular toxicities, and adherence to established cardiovascular guidelines.

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Keywords: Alkylating Agents, Angiogenesis Inhibitors, Angiotensin-Converting Enzyme Inhibitors, Anthracyclines, Antibodies, Monoclonal, Antimetabolites, Atherosclerosis, Blood Pressure, Bone Marrow Transplantation, Cardiomyopathies, Cardiotoxicity, Carotid Arteries, Carotid Stenosis, Coronary Artery Bypass, Coronary Artery Disease, Diabetes Mellitus, Hypertension, Hypertension, Pulmonary, Indazoles, Infarction, Myocardial Infarction, Neoplasms, Germ Cell and Embryonal, Platelet Aggregation, Pulmonary Veno-Occlusive Disease, Risk Factors, Stroke, Thalidomide, Thrombosis, Vascular Endothelial Growth Factor A, Vasoconstriction, Vasoconstrictor Agents, Vasodilator Agents, Venous Thromboembolism, Venous Thrombosis

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