Cardiovascular Toxicity Related to Cancer Treatment: A Pragmatic Approach to the American and European Cardio-Oncology Guidelines

Abstract

The considerable progress made in the field of cancer treatment has led to a dramatic improvement in the prognosis of patients with cancer. However, toxicities resulting from these treatments represent a cost that can be harmful to short- and long-term outcomes. Adverse events affecting the cardiovascular system are one of the greatest challenges in the overall management of patients with cancer, as they can compromise the success of the optimal treatment against the tumor. Such adverse events are associated not only with older chemotherapy drugs such as anthracyclines but also with many targeted therapies and immunotherapies. Recognizing this concern, several American and European governing societies in oncology and cardiology have published guidelines on the cardiovascular monitoring of patients receiving potentially cardiotoxic cancer therapies, as well as on the management of cardiovascular toxicities. However, the low level of evidence supporting these guidelines has led to numerous discrepancies, leaving clinicians without a consensus strategy to apply. A cardio-oncology expert panel from the French Working Group of Cardio-Oncology has undertaken an ambitious effort to analyze and harmonize the most recent American and European guidelines to propose roadmaps and decision algorithms that would be easy for clinicians to use in their daily practice. In this statement, the experts addressed the cardiovascular monitoring strategies for the cancer drugs associated with the highest risk of cardiovascular toxicities, as well as the management of such toxicities.

Keywords: cancer; cardiotoxicity; cardio‐oncology; guidelines.

Figure 1. Pragmatic approach for monitoring patients treated with anthracyclines (A) and human epidermal growth factor‐2 (HER2) inhibitors (B).

*The cardio‐oncological evaluation will systematically include at least 1 visit with:

1. Clinical consultation (including BP measurement).

2. ECG.

3. Blood glucose, lipid profile, and glomerular filtration rate calculation should be evaluated before initiation of anthracyclines and HER2 inhibitors. Recheck at least at 1 year, 2 years, and periodically thereafter for patients who received anthracyclines.

4. TTE including measurements of LVEF measurements (ideally 3‐dimensional but at least 2‐dimensional Simpson biplane method) and GLS. In the absence of GLS quantification of LV longitudinal function, use mitral annular displacement by M‐mode echocardiography and/or peak systolic velocity of the mitral annulus by pulsed‐wave DTI.

5. LV contrast agents could be potentially useful in 2‐dimensional echocardiography.

6. CMR is recommended if the quality of TTE is suboptimal.

7. Use the same imaging modality for monitoring.

8. Actively manage modifiable cardiovascular risk factors and diseases.

9. Encourage exercise on a regular basis and healthy dietary habits.

^†For monitoring, assays should be performed by the same laboratory (same type of troponin, same method of measurement) and at the same time (before or within 24 hours after each cycle). Troponin+ if >99th percentile of the upper reference limit or significantly increased compared with baseline. ACE_i indicates angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, β‐blocker; BNP, B‐type natriuretic peptide; BP, blood pressure; CMR, cardiac magnetic resonance; CV, cardiovascular; DTI, Doppler tissue imaging; GLS, global longitudinal strain; LV, left ventricular; LVEF, left ventricular ejection fraction; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; and TTE, transthoracic echocardiogram.

Figure 2. Pragmatic approach for monitoring patients treated with VEGF_i and mTOR_is (A), Bcr‐Abl_is (B), proteasome inhibitors (C), and ibrutinib (D).

*The cardio‐oncological evaluation will systematically include at least 1 visit with

1. Clinical consultation (including BP measurement).

2. ECG.

3. Blood glucose, lipid profile, and glomerular filtration rate calculation should be evaluated before initiation of these drugs. Recheck at least every 3 months for 1 year, then every 6 months for patients who received VEGF_i, mTOR_i, and Bcr‐Abl_i.

4. TTE including measurements of LVEF measurements (ideally 3‐dimensional but at least 2‐dimensional Simpson biplane method) and GLS. In the absence of GLS quantification of LV longitudinal function, use mitral annular displacement by M‐mode echocardiography and/or peak systolic velocity of the mitral annulus by pulsed‐wave DTI.

5. LV contrast agents could be potentially useful in 2‐dimensional echocardiography.

6. CMR imaging is recommended if the quality of TTE is suboptimal.

7. Use the same imaging modality for monitoring.

8. Actively manage modifiable cardiovascular risk factors and diseases.

9. Encourage to exercise on a regular basis and healthy dietary habits.

^†Transthoracic echocardiogram (TTE) is recommended for baseline pulmonary pressure assessment. ^‡TTE and B‐type natriuretic peptide (BNP)/NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) must not be performed the day of proteasome inhibitor infusion. ^§Holter‐ECG monitoring can be considered even in asymptomatic patients to asymptomatic atrial fibrillation or ventricular arrhythmia. Bcr‐Abl_i indicates Bcr‐Abl kinase inhibitor; BP, blood pressure; CV, cardiovascular; CMR, cardiac magnetic resonance; DTI, Doppler tissue imaging; GLS, global longitudinal strain; LV, left ventricular; LVEF, left ventricular ejection fraction; mTOR_i, mammalian target of rapamycin inhibitor; PAD, peripheral artery disease; TK_i, tyrosine kinase inhibitor; and VEGF_i, vascular endothelial growth factor inhibitor.

Figure 3. Pragmatic approach for monitoring patients treated with immune checkpoint inhibitors.

*For monitoring, assays should be performed by the same laboratory (same type of troponin, same method of measurement) and before each administration. Troponin+ if >99th percentile of the upper reference limit or significantly increased compared with baseline. CV indicates cardiovascular; irAEs, immune‐related adverse events.

Figure 4. Definitions and management of overt cancer therapy–related left ventricular systolic dysfunction (A) and early cancer therapy–related myocardial toxicity (B).

*The cardio‐oncological evaluation will systematically include at least 1 visit with

1. Clinical consultation (including BP measurement).

2. ECG.

3. Blood glucose, lipid profile, glomerular filtration rate calculation.

4. TTE including measurements of LVEF measurements (ideally 3‐dimensional but at least 2‐dimensional Simpson biplane method) and GLS. In the absence of GLS quantification of LV longitudinal function, use mitral annular displacement by M‐mode echocardiography and/or peak systolic velocity of the mitral annulus by pulsed‐wave DTI.

5. LV contrast agents could be potentially useful in 2‐dimensional echocardiography.

6. CMR is recommended if the quality of TTE is suboptimal.

7. Use the same imaging modality for monitoring.

8. Actively manage modifiable cardiovascular risk factors and diseases.

9. Encourage to exercise on a regular basis and healthy dietary habits.

^†Heart failure (HF) therapy should be continued indefinitely unless normal systolic left ventricular (LV) function remains stable after cessation of HF therapy and no further cancer therapy is planned. In patients with trastuzumab‐induced cardiac dysfunction, HF treatment can be stopped after normalization. ^‡If recovery to the initial LV ejection fraction (LVEF) to within 5 units. ^§If recovery of at least 10 units of LVEF but still >5 units below baseline. ^||For monitoring, assays should be performed by the same laboratory (same type of troponin, same method of measurement) and at the same time (before or within 24 hours after each cycle). ^#Low level of evidence for this strategy. Angiotensin‐converting enzyme inhibitors (ACE_is) and β‐blockers (BBs) can be stopped if normal systolic LV function remains stable after cessation of HF therapy and no further cancer therapy is planned. ARB indicates angiotensin receptor blocker; BNP, B‐type natriuretic peptide; BP, blood pressure; CMR, cardiac magnetic resonance; CV, cardiovascular; DTI, Doppler tissue imaging; GLS, global longitudinal strain; HFrEF, heart failure with reduced ejection fraction; LVEF, left ventricular ejection fraction; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; NYHA, New York Heart Association; and TTE, transthoracic echocardiogram.

Figure 5. Definitions and management of cancer therapy–related hypertension (A), QTc interval prolongation (B), atrial fibrillation (C), and immune checkpoint inhibitors–related myocarditis (D).

*The cardio‐oncological evaluation will systematically include at least one visit with

1. Clinical consultation (including BP measurement).

2. ECG.

3. Blood glucose, lipid profile, glomerular filtration rate calculation.

4. TTE including measurements of LVEF measurements (ideally 3‐dimensional but at least 2‐dimensional Simpson biplane method) and GLS. In the absence of GLS quantification of LV longitudinal function, use mitral annular displacement by M‐mode echocardiography and/or peak systolic velocity of the mitral annulus by pulsed‐wave DTI.

5. LV contrast agents could be potentially useful in 2‐dimensional echocardiography.

6. CMR is recommended if the quality of TTE is suboptimal.

7. Use the same imaging modality for monitoring.

8. Actively manage modifiable cardiovascular risk factors and diseases.

9. Encourage to exercise on a regular basis and healthy dietary habits.

^†Hypertension emergencies are situations in which grade 3 hypertension (systolic arterial pressure ≥180 mm Hg and/or diastolic arterial pressure ≥110 mm Hg) is associated with acute hypertension‐mediated organ damage (eg, acute heart failure [HF], acute aortic dissection, acute coronary syndrome, retina hemorrhages and/or edema, encephalopathy, acute renal failure). ^‡ Fridericia correction ($\text{QTcF}=\text{QT}/\sqrt[3]{\text{RR}}$) should be preferred to Bazett correction ($\text{QTcB}=\text{QT}/\sqrt{\text{RR}}$). If possible, manual measurement is recommended using DII first, or V5 or V6, or DI, or in the best lead (stepwise method). ^§Several drugs increase QTc interval: antibiotics, antiemetics, CNS drugs.list available on https://www.crediblemeds.org/index.php/login/dlcheck. ^||β‐Blockers present no/few drug‐drug interaction with cancer treatments, particularly atenolol and nebivolol. Avoid digoxin and calcium channel blockers (verapamil, diltiazem). ^#The potential for drug‐drug interactions (through P‐glycoprotein and cytochrome P450 systems) and QTc interval prolongation must be considered when associating antiarrhythmic with an anticancer drugs. **Congestive heart failure, hypertension, age ≥75, diabetes mellitus, stroke, vascular disease, age 65 to 74, and sex (women) (CHA₂DS₂‐VASc) and hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly (>65 years), drugs/alcohol (HAS‐BLED) scores have not been validated in patients with cancer. Cancer associated with higher bleeding risks are lung, gastric, and pancreatic cancers. ^††No anticoagulation if major bleeding risk or estimated life expectancy <3 months or thrombocytopenia <50 000. ^‡‡For monitoring, assays should be peformed by the same laboratory (same type of troponin, same method of measurement) and before each administration. Troponin+ if >99th percentile of the URL or significantly increased compared with baseline. ^§§Hemodynamic instability OR electric instability OR increasing troponin OR decreasing left ventricular ejection fraction (LVEF). ^||||Strategies are alphabetically presented. There is no consensus. ^##Consider no dosage change or other immunosuppressive therapy if troponin does not recover to baseline value or rise again. ACE_i indicates angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, β‐blocker; BP, blood pressure; CK, creatine phosphokinase; CMR, cardiac magnetic resonance; CV, cardiovascular; DOAC, direct oral anticoagulant; DTI, Doppler tissue imaging; GLS, global longitudinal strain; ICI, immune checkpoint inhibitor; irAE, immune‐related adverse event; LMWH, low‐molecular‐weight heparin; LV, left ventricular; PET, positron emission tomography; and TTE, transthoracic echocardiogram.