Preamble
Background
Therapy type | Therapy subtypes | Cancer therapy-induced dysfunction | Myocarditis/pericarditis | Arrhythmias/QT prolongation | Vascular toxicity | Hypertension |
---|---|---|---|---|---|---|
Conventional chemotherapies | Anthracyclines (doxorubicin, epirubicin) | ✓ | ||||
Alkylating agents (cyclophosphamide, melphalan) | ✓ | ✓ | ✓ | |||
Antimetabolites (5-FU, capecitabine, cytarabine) | ✓ | ✓cytarabine | ✓ | |||
Microtubule-bonding agents (paclitaxel) | ✓ | ✓ | ||||
Platinum based therapy (cisplatin) | ✓ | ✓ | ||||
Antibiotic (bleomycin) | ✓ | |||||
Immunomodulatory drugs (thalidomide, lenalidomide, pomalidomide) | ✓ | ✓ | ✓ | |||
Targeted agents | Proteasome inhibitors (bortezomib, carfilzomib) | ✓ | ✓ | ✓ | ||
HDAC inhibitors (panobinostat, vorinostat) | ✓ | |||||
CDK4/CDK6 inhibitors (ribociclib) | ✓ | |||||
mTOR inhibitors (everolimus) | ✓ | ✓ | ✓ | ✓ | ||
HER2 inhibitors (pertuzumab, trastuzumab, lapatinib, adotrastuzumabemtansin) | ✓ | |||||
VEGF inhibitors (bevacizumab, ramucirumab, aflibercept, sunitinib) | ✓ | ✓bevacizumab | ✓ | ✓ | ||
BCR-ABL1 inhibitors (dasatinib, nilotinib, ponatinib, bosutinib, imatinib) | ✓pontinib | ✓ | ✓ | ✓ | ✓ | |
BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib) | ✓ | ✓ibrutinib | ||||
ALK inhibitors (alectinib, ceritinib, crizotinib, brigatinib, lorlatinib) | ✓ceritinib | ✓ | ✓ | ✓brigatinib | ||
BRAF inhibitors (dabrafenib, vemurafenib, encorafenib) | ✓ | ✓ | ✓encorafenib | ✓ | ||
MEK inhibitors (binimetinib, cobimetinib, trametinib) | ✓ | ✓ | ✓binimetinib | ✓ | ||
Multitarget (sorafenib, sunitinib, pazopanib, vandetanib, lenvatinib, regorafenib, cabozantinib) | ✓ | ✓ | ✓ | ✓ | ||
EGFR inhibitors (panitumumab, necitumumab) | ✓panitumumab | ✓necitumumab | ✓panitumumab | |||
Immunotherapies | Immune checkpoint inhibitors (ipilimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, cemiplimab, dostarlimab) | ✓ | ✓ | ✓ | ✓ | |
CAR-T cell therapy (tisagenlecleucel, axicabtagene cioleucel, lisocabtagene maraleucel, brexucabtagene autoleucel, idecabtagene) | ✓ | ✓ | ✓ | ✓ | ||
Hormonal therapy | abiraterone, anastrozolem apalutamide, bicalutamide, darolutamide, enzamestane, exemestane, flutamine, letrozole, nilutamide | ✓ | ✓ | |||
Radiation therapy | ✓ | ✓ | ✓ | ✓ |
Cardiac assessment of patients with signs suspicious of cardiotoxic origin
Cardiotoxicity type | Category | Severity | Diagnosis criteria |
---|---|---|---|
Cancer therapy-related cardiac dysfunction (CTRCD) | Asymptomatic (with or without additional biomarkers, LVEF values are based on 2D echocardiography) | Mild | LVEF ≥ 50% AND new relative decline in GLS by > 15% from baseline AND/OR new rise in cardiac biomarkers (troponin I/T > 99th percentile, BNP ≥ 35 pg/ml, NT-proBNP ≥ 125 pg/ml) |
Moderate | New LVEF reduction by ≥ 10 percentage points to an LVEF of 40–49% New LVEF reduction by < 10 percentage points to an LVEF of 40–49% AND new relative decline in GLS by > 15% from baseline AND/OR new rise in cardiac biomarkers | ||
Severe | New LVEF reduction to < 40% | ||
Symptomatic (with LVEF and supported diagnostic biomarkers) | Mild | Mild HF symptoms, no intensification of therapy required | |
Moderate | Need for outpatient intensification of diuretic and HF therapy | ||
Severe | HF hospitalization | ||
Very severe | Requiring inotropic support, mechanical circulatory support, or consideration for transplantation | ||
Myocarditis | Pathohistological diagnosis Multifocal inflammatory cell infiltrates with overt cardiomyocyte loss by light microscopy of cardiac tissue samples or Clinical diagnosis A troponin elevation with 1 major criterion or a troponin elevation with 2 minor criteria after exclusion of acute coronary syndrome or acute infectious myocarditis based on clinical suspicion | Severe | Hemodynamic instability, heart failure requiring non-invasive or invasive ventilation, complete or high-grade heart block, and/or no significant ventricular arrhythmia |
Non-severe (clinically significant) | Symptomatic but hemodynamically and electrically stable, may have reduced LVEF, no features of severe disease | ||
Major criterion CMR diagnostic for acute myocarditis (modified Lake Louise criteria) Minor criteria •Clinical syndrome •Ventricular arrhythmia and/or new conduction system disease •Decline in cardiac function •Other immune-related adverse events •Suggestive CMR | Smoldering (subclinical) | Incidentally diagnosed myocarditis without any clinical signs or symptoms | |
Steroid refractory | Non-resolving or worsening myocarditis (clinical worsening or persistent troponin elevation after exclusion of other etiologies) despite high-dose methylprednisolone | ||
Vascular toxicity | Asymptomatic | Atherosclerosis | Coronary artery disease: new corona artery stenosis > 50% on coronary computed tomography angiogram or > 70% on coronary angiogram, or newly abnormal electrocardiogram (ECG), nuclear or echo stress test 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 or chance in ABI from baseline by − 0.15 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 baseline |
Thrombosis | Venous thrombosis: new characteristic features and Duplex ultrasound, contrast CT, or venogram Arterial thrombosis: new characteristic features on ultrasound or angiogram, or optical coherence tomography | ||
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 baseline Coronary epicardial: new coronary vasoconstriction (reduction in coronary artery diameter) in response to acetylcholine infusion Coronary microvascular: new < 50% increase in coronary blood flow in response to acetylcholine infusion, or a coronary flow reserve < 2 in response to adenosine | ||
Symptomatic | Stroke | 2018 AHA/ASA Guidelines for the Early Management of Patients With Ischemic Stroke An Updated Definition of Stroke for the 21st Century Stroke | |
Transient ischemic attack | |||
Myocardial infarction | 4th Universal Definition of MI | ||
Acute coronary syndromes | 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction 2014 AHA/ACC Guideline for the Management of Patients with Non–ST-Elevation Acute Coronary Syndromes 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation | ||
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) | ||
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) | ||
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) International standardization of diagnostic criteria for vasospastic angina | ||
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) International standardization of diagnostic criteria for microvascular angina | ||
Raynaud’s phenomenon | Meeting the diagnostic criteria of an international consensus panel of recurrent episodes bilateral blanching or tricolor change of the fingers | ||
Hypertension | Normal SBP ≤ 130 mmHg And DBP ≤ 80 mmHg | Treatment threshold for hypertension before, during, and off therapy/cancer survivors | CVD or ASCVD risk ≥ 10%: ≥ 130 mmHg systolic and/or ≥ 80 mmHg diastolic Otherwise: ≥ 140 mmHg systolic and/or ≥ 90 mmHg diastolic |
Cancer therapy holding threshold | ≥ 180 mmHg systolic and/or ≥ 110 mmHg diastolic | ||
Exaggerated hypertensive response | Systolic BP increase > 20 mmHg or mean arterial BP increase > 15 mmHg | ||
Hypertensive emergency response | Very high BP elevations associated with acute hypertension-mediated organ damage (heart, retina, brain, kidneys, and large arteries), therefore requiring immediate BP reduction to limit extension or promote regression of target organ damage | ||
QT prolongation and arrhythmias | QTc prolongation | QTcF < 480 ms | Acceptable: continue current treatment |
QTcF 480–500 ms | Prolonging: proceed with caution; minimize other QT-prolonging medications, replete electrolytes | ||
QTcF > 500 ms | Prolonged: stop treatment and evaluate. May require dose reduction or alternative therapy | ||
Arrhythmias | Ventricular arrhythmia | 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death | |
Ventricular tachycardia (VT), including polymorphic VT (torsades de pointes) | |||
Ventricular fibrillation | |||
Atrial fibrillation | 2020 ESC Guidelines for Management of Atrial Fibrillation 2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation | ||
Atrial flutter | |||
Atrial tachycardia | 2019 ESC Guidelines on Supraventricular Tachycardia 2015 ACC/AHA/HRS Guideline for the Management of Adult Patients With Supraventricular Tachycardia: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society | ||
Supraventricular tachycardia | |||
Sinus tachycardia | |||
Sinus bradycardia | 2018 ACC/AHA/HRS Guideline on the evaluation and management of patients with bradycardia and cardiac conduction delay | ||
Sick sinus syndrome | |||
Atrioventricular block first, second and third degree | |||
Conduction disorder (disease) |
Nuclear imaging of therapy-related cardiotoxicity in oncology patients
Modality | Parameters | Advantages | Disadvantages |
---|---|---|---|
ERNA | -Ventricular volumes -Ejection fractions -Systolic and diastolic function -Wall motion -Phase analysis | -Highly standardized -Excellent reproducibility -Observer independent -Virtually no restrictions regarding patient selection (e.g., obesity, cardiac devices) -Evaluation of both right and left ventricles | -No assessment of myocardial perfusion |
MPI (SPECT) | -Left ventricular volumes -Left ventricular ejection fraction -Systolic and diastolic function -Wall motion -Phase analysis -Myocardial perfusion (qualitatively) | -Highly standardized -Good reproducibility -Virtually no restrictions regarding patient selection (e.g., obesity, cardiac devices) | -No assessment of right ventricle |
MPI (PET) | -Ventricular volumes -Ejection fractions -Systolic and diastolic function -Wall motion -Myocardial perfusion (quantitatively) | -Highly standardized -Good reproducibility -Quantification (MBF, MFR) -Assessment of epicardial and microvascular disease -Detection of even subtle changes | -Limited availability -Relatively expensive |
Innervation imaging (e.g., MIBG SPECT, HED PET) | -Distribution and integrity of sympathetic innervation -Sympathetic tone (tracer washout) -Novel tracers, e.g., receptor density | -Changes in innervation appear before structural or functional changes of the heart | -Limited data |
Glucose metabolism (2-[18F]FDG PET) of the myocardium | -Regional changes in 2-[18F]FDG uptake -Quantitative parameters (SUV) | -Changes appear before structural or functional changes of the heart -Patients often receive the examination anyways for their oncological disease | -Many influential factors on 2-[18F]FDG uptake (not specific for cardiotoxicity) -Limited data |
Procedure | Radiotracer | Effective dose per MBq | Recommended activity | Resulting effective dose | References |
---|---|---|---|---|---|
ERNA | [99mTc]Tc-RBCs | 0.0047 mSv/MBq | 555–1110 MBq | 2.6–5.2 mSv | [24] |
SPECT MPI | [99mTc]Tc-labeled perfusion tracers | [99mTc]Tc-tetrofosmin (stress and rest): 0.0058 and 0.0063 mSv/MBq, respectively [99mTc]Tc-sestamibi (stress and rest): 0.0066 and 0.0070 mSv/MBq, respectively | Depending on protocol (1-day vs. 2-day protocol, stress only, CZT vs. conventional camera etc.): 150–400 MBq (stress), 180–1200 MBq (rest) | 0.9–11.2 mSv | |
PET MPI | [15O]H2O | 0.0011 mSv/MBq | 2 × 400 MBq (stress/rest) | 0.8 mSv | |
82Rb | 0.001 mSv/MBq | 2 × 10 MBq/kg (stress/rest) | 1.5 mSv | ||
[13N]NH3 | 0.0027 mSv/MBq | 2 × 400 MBq (stress/rest) | 1.8 mSv | ||
Innervation SPECT | [123I]mIBG | 0.037 mSv/MBq | 111–370 MBq | 4.1 – 13.7 mSv | [114] |
Viability/inflammation PET | 2-[18F]FDG | 0.019 mSv/MBq | 185–555 MBq | 3.5–10.5 mSv | |
Vascular toxicity PET | 2-[18F]FDG | 0.019 mSv/MBq | 3–4 MBq/kg | 4–7.5 mSv |
Two/three-dimensional radionuclide angiography
Baseline ERNA | Treatment initiation | Serial monitoring (with respect to chemotherapy) | Treatment discontinuation |
---|---|---|---|
LVEF ≥ 50% | Yes | •At 250–300 mg/m2 dose •At 400 mg/m2 dose if high risk* •At 450 mg/m2 dose •Prior to each dose > 450 mg/m2 | If LVEF decreases ≥ 10% (EF units) from baseline and reaches < 50% |
LVEF 30–50% | Yes | •Prior to each subsequent dose | If LVEF decreases ≥ 10% (EF units) from baseline, or reaches ≤ 30% |
LVEF ≤ 30% | No | –/– | –/– |
Myocardial perfusion imaging
SPECT
PET—absolute quantification of myocardial blood flow and flow reserve
Imaging of sympathetic innervation
Glucose metabolism
Assessment of myocardial damage: [99mTc]Tc-annexin/[111In]In-antimyosin, fibroblast activation
2-[18F]FDG PET for assessment of vascular toxicity
Future perspectives
Promising imaging approaches for future studies
Target | Involved processes | Tracers | Potential applications | Ref |
---|---|---|---|---|
Somatostatin receptors (SSTR) | Overexpression on macrophages | [68Ga]Ga-DOTATOC, [68Ga]Ga-DOTATATE, [68Ga]Ga-DOTANOC | Inflammatory processes (e.g., myocarditis, pericarditis, vasculitis) | |
αvβ3 integrin receptor | Cell adhesion, neoangiogenesis, overexpressed on macrophages | [18F]F-galacto-RGD, [68Ga]Ga-PRGD2, [18F]F-fluciclatide | Neoangiogenesis, inflammatory processes | [104] |
Fibroblast activation protein (FAP) | Activation of fibroblasts | Various 68Ga-labeled inhibitors of FAP (e.g., [68Ga]Ga-FAPI-04, [68Ga]Ga-FAPI-46) | Myocardial damage | [73] |
Norepinephrine transporter (NET) | Sympathetic innervation of the heart | [18F]F-flubrobenguane | Denervation as early sign of damage to the heart | [101] |
Mitochondrial membrane potential | Dysfunction of mitochondrial membrane | [18F]F-MitoPhos, [68Ga]Ga-Galmydar | Mitochondrial dysfunction as early sign of cardiotoxicity | |
Reactive oxygen species (ROS) | Superoxide production in processes such as myocardial apoptosis or necrosis | [18F]F-DHMT | ROS generation as early sign of cardiotoxicity | (107) |