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. 2021 Dec 14;43(4):280–299. doi: 10.1093/eurheartj/ehab674

Table 3.

Definitions for Vascular Toxicities with Cancer Therapies

CTCAE Version 5*  
Event Definition Grades
Arterial injury A finding of damage to an artery.

  • Grade 1: Asymptomatic diagnostic finding; intervention not indicated

  • Grade 2: Symptomatic; repair or revision not indicated

  • Grade 3: Severe symptoms; limiting self care activities of daily living (ADL); repair or revision indicated

  • Grade 4: Life-threatening consequences; evidence of end organ damage; urgent operative intervention indicated
Arterial thromboembolism A disorder characterized by occlusion of an arterial vessel by a blood clot that develops in an artery.

  • Grade 3: urgent intervention indicated

  • Grade 4: life-threatening consequences, hemodynamic or neurologic instability; organ damage; loss of extremity(ies)
Chest pain (cardiac) A disorder characterized by substernal discomfort due to insufficient myocardial oxygenation e.g., angina pectoris.

  • Grade 1: Mild pain

  • Grade 2: Moderate pain; pain on exertion; limiting instrumental ADL; hemodynamically stable

  • Grade 3: Pain at rest; limiting self care ADL; cardiac catheterization; new onset cardiac chest pain; unstable angina
Cerebrovascular ischemia A disorder characterized by a decrease or absence of blood supply to the brain caused by obstruction (thrombosis or embolism) of an artery resulting in neurological damage.

  • Grade 1:Asymptomatic; clinical or diagnostic observations only; intervention not indicated

  • Grade 2: Moderate symptoms
Myocardial infarction A disorder characterized by gross necrosis of the myocardium; this is due to an interruption of blood supply to the area.

  • Grade 2: Symptoms with moderate activity or exertion

  • Grade 3: Severe with symptoms at rest or with minimal activity or exertion; intervention indicated; new onset of symptoms

  • Garde 4: Life-threatening consequences; urgent intervention indicated (e.g., continuous intravenous (IV) therapy or mechanical hemodynamic support)
Peripheral ischemia A disorder characterized by impaired circulation to an extremity.

  • Grade 2: Brief (<24 hrs) episode of ischemia managed medically and without permanent deficit

  • Grade 3: Prolonged (>=24 hrs) or recurring symptoms and/or invasive intervention indicated

  • Grade 4: Life-threatening consequences; evidence of end organ damage; urgent operative intervention indicated
Stroke A disorder characterized by a decrease or absence of blood supply to the brain caused by obstruction (thrombosis or embolism) of an artery resulting in neurological damage.

  • Grade 1: Incidental radiographic findings only

  • Grade 2: Mild to moderate neurologic deficit; limiting instrumental ADL

  • Grade 3: Severe neurologic deficit; limiting self care ADL; hospitalization

  • Grade 4: Life-threatening consequences; urgent intervention indicated
Thromboembolic event A disorder characterized by occlusion of a vessel by a thrombus that has migrated from a distal site via the blood stream.

  • Grade 1: Medical intervention not indicated (e.g., superficial thrombosis)

  • Grade 2: Medical intervention indicated

  • Grade 3: Urgent medical intervention indicated (e.g., pulmonary embolism or intracardiac thrombus)

  • Grade 4: Life-threatening consequences with hemodynamic or neurologic instability
Transient ischemic attack A disorder characterized by a brief attack (less than 24 hours) of cerebral dysfunction of vascular origin, with no persistent neurological deficit.

  • Grade 1: Mild neurologic deficit with or without imaging confirmation

  • Grade 2: Moderate neurologic deficit with or without imaging confirmation
Vasculitis A disorder characterized by inflammation involving the wall of a vessel.

  • Grade 1: Asymptomatic, intervention not indicated

  • Garde 2: Moderate symptoms, medical intervention indicated

  • Grade 3: Severe symptoms, medical intervention indicated (e.g., steroids)

  • Grade 4: Life-threatening consequences; evidence of peripheral or visceral ischemia; urgent intervention indicated
Vascular disorder

  • Grade 1: Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated

  • Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL

  • Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of existing hospitalization indicated; limiting self care ADL

  • Grade 4: Life-threatening consequences; urgent intervention indicated
Venous injury A finding of damage to a vein

  • Grade 1: Asymptomatic diagnostic finding; intervention not indicated

  • Grade 2: Symptomatic (e.g., claudication); repair or revision not indicated

  • Grade 3: Severe symptoms; limiting self care ADL; repair or revision indicated

  • Grade 4: Life-threatening consequences; evidence of end organ damage; urgent operative intervention indicated
IC-OS 2021 Consensus
Asymptomatic vascular toxicity
Atherosclerosis

  • Coronary artery disease:

  • New coronary artery stenosis >50% on coronary computed tomography (CT) angiogram or >70% on coronary angiogram, or newly abnormal electrocardiogram (ECG), nuclear or echo stress test77

  • Peripheral arterial disease:

  • New ankle-brachial index (ABI) value ≤ 0.9 is considered abnormal, with 0.7-0.9 being mildly reduced, 0.4-0.69 moderately reduced, and <0.4 severely reduced; ABI value >1.3 is suggestive of non-compressible vessels, or

  • Chance in ABI from baseline by -0.1575

  • Carotid artery disease:

  • New intima media thickness (IMT) >0.9 mm or new plaque on carotid ultrasound, or

  • Change in IMT >0.04/year from baseline76
Thrombosis

  • Venous thrombosis:

  • New characteristic features on Duplex ultrasound, contrast CT, or venogram

  • Arterial thrombosis:

  • New characteristic features on ultrasound or angiogram, or optical coherence tomography (OCT)
Abnormal vasoreactivity

  • Peripheral:

  • New flow-mediated dilation of the brachial artery (FMD) < 7.1% or reactive hyperemia index (RHI) <2 on Endo-PAT, or

  • Change in FMD or RHI by >50% from baseline69–72

  • Coronary epicardial:

  • New coronary vasoconstriction (reduction in coronary artery diameter) in response to acetylcholine infusion.73

  • Coronary microvascular:

  • New <50% increase in coronary blood flow in response to acetylcholine infusion, or a coronary flow velocity reserve <2 in response to adenosine.74
Symptomatic vascular toxicity
Stroke

  • 2018 AHA/ASA Guidelines for the Early Management of Patients With Ischemic Stroke87

  • An Updated Definition of Stroke for the 21st Century Stroke:88
Transient ischemic attack

  • 2018 AHA/ASA Guidelines for the Early Management of Patients With Acute Ischemic Stroke87

  • An Updated Definition of Stroke for the 21st Century Stroke:88
Myocardial infarction 4th Universal Definition of MI86
Acute coronary syndromes

  • 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction82

  • 2014 AHA/ACC Guideline for the Management of Patients With Non–ST-Elevation Acute Coronary Syndromes83

  • 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation84

  • 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation85
Chronic coronary syndromes 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes: The Task Force for the diagnosis and management of chronic coronary syndromes of the European Society of Cardiology (ESC)81
Peripheral arterial disease 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS)80
Vasospastic angina 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes: The Task Force for the diagnosis and management of chronic coronary syndromes of the European Society of Cardiology (ESC)81
International standardization of diagnostic criteria for vasospastic angina89
Microvascular angina 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes: The Task Force for the diagnosis and management of chronic coronary syndromes of the European Society of Cardiology (ESC)81
International standardization of diagnostic criteria for microvascular angina90
Raynaud’s phenomenon Meeting the diagnostic criteria of an international consensus panel of recurrent episodes bilateral blanching or tricolor change of the fingers.78  ,  79

*Grade 5 = death.