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

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.

angiotensin‐converting enzyme inhibitor

atrial fibrillation

angiotensin receptor blocker

adverse event

American Society of Clinical Oncology

β‐blocker

Bcr‐Abl kinase inhibitor

blood pressure

congestive heart failure, hypertension, age ≥75, diabetes mellitus, stroke, vascular disease, age 65–74, and sex (women)

European Society of Cardiology

European Society for Medical Oncology

global longitudinal strain

hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly (>65 years), drugs/alcohol

human epidermal growth factor‐2 inhibitor

heart failure

immune checkpoint inhibitor

left ventricular ejection fraction

left ventricular systolic dysfunction

proteasome inhibitor

vascular endothelial growth factor inhibitor

Cardiovascular diseases in patients with cancer represent a major challenge for cardiologists and oncologists because of considerable advances in cancer treatment, which have increased the life expectancy of patients at the cost of short‐ and long‐term adverse drug reactions, especially in the cardiovascular system. The emergence of the cardio‐oncology specialty is the result of awareness that patients treated for cancer may represent a new group with a high level of cardiovascular risk and a set of specific management needs. , , As a result, cardiologists and oncologists are currently facing a dramatic increase in the number of patients presenting with a combination of cancer, cancer treatment, and cancer treatment–related cardiovascular diseases. , , Several international guidelines and position articles have been published on the cardiovascular monitoring and management of patients treated with cancer drugs. , , , , , , However, the low level of evidence supporting these statements has led to numerous discrepancies between them, rendering it difficult for clinicians to propose a practical approach adapted to each clinical situation. Therefore, a cardio‐oncology expert panel was convened to develop roadmaps and pragmatic algorithms that could be easily used by clinicians. This panel, from the French Working Group of Cardio‐Oncology, was composed of cardiologists, oncologists, hematologists, and pharmacologists with expertise in cardiotoxicity. They analyzed and compared the key components of the pathways recommended by the most recent guidelines from the American and European societies of both oncology and cardiology; they then proposed pragmatic approaches based on harmonization of these guidelines and the most recent published studies.

This statement analyzed the guidelines from the American Society of Clinical Oncology (ASCO‐2017 and ASCO‐2018 ), the European Society for Medical Oncology (ESMO‐2017 and ESMO‐2020 ), and the European Society of Cardiology (ESC‐2016 ). The ESMO‐2017 and ASCO‐2018 guidelines were specific to immune checkpoint inhibitor (ICi)–related toxicity. For cardiovascular monitoring strategies, only the cancer drugs associated with a high risk of cardiovascular toxicity were analyzed, including anthracyclines, human epidermal growth factor‐2 inhibitors (HER2is), vascular endothelial growth factor inhibitors (VEGFis), Bcr‐Abl kinase inhibitors (Bcr‐Ablis), proteasome inhibitors (proteasomeis), ICis, and ibrutinib. Cardiovascular complications related to anticancer hormonotherapy and radiotherapy are not addressed in this article. This work does not provide detailed information regarding the cardiovascular toxicities associated with each cancer treatment because these data are available in the existing guidelines; rather, it provides a more practical harmonization that can be useful in daily clinical practice for physicians who care for patients with cancer.

Cardiovascular Monitoring During Cancer Treatment

Definition of High‐Risk Patients and the Concept of the “Cardio‐Oncological Evaluation”

All of the guidelines emphasize the need to identify patients with an increased risk of developing cardiovascular toxicity, beginning at treatment initiation and continuing for years after the end of cancer treatment. However, differences exist in the definition of high‐risk patients and the recommended strategies for investigation (Table S1). Although slightly different, all of the definitions include patients with previous cardiovascular diseases or risk factors, high‐dose anthracycline, and combination therapy based on several studies. , , The pragmatic harmonized definition proposed by the working group is shown in Table 1.

Table 1

Patients at Higher Risk for Cardiovascular Toxicity

High‐dose anthracycline (eg, doxorubicin ≥250 mg/m2, epirubicin ≥600 mg/m2) High‐dose radiotherapy (≥30 Gy) where the heart is in the treatment field Lower‐dose anthracycline (eg, doxorubicin <250 mg/m2, epirubicin <600 mg/m2) or HERis or VEGFis or proteasomeis or Bcr‐Ablis and presence of any of the following factors: ○ Age ≥60 y ○ Lower‐dose radiotherapy (<30 Gy) where the heart is in the treatment field ○ ≥2 Risk factors, including smoking, hypertension, diabetes mellitus, dyslipidemia, chronic renal insufficiency, and obesity Previous heart disease Elevated cardiac biomarkers* before initiation of anticancer therapy

Bcr‐Ablis indicates Bcr‐Abl kinase inhibitors; HERis, human epidermal growth factor‐2 inhibitors; proteasomeis, proteasome inhibitors; and VEGFis, vascular endothelial growth factor inhibitors.

N‐terminal pro‐B‐type natriuretic peptide (or B‐type natriuretic peptide) and/or troponin.

For a long time, cardiological assessment of patients receiving cancer therapy has been limited to the measurement of left ventricular ejection fraction (LVEF). It is now clearly established that this evaluation is insufficient and should include a more comprehensive cardiovascular risk evaluation allowing earlier detection of myocardial toxicities as well as other cardiovascular toxicities (eg, hypertension, QTc interval prolongation, arrhythmias, and vascular diseases). , , Therefore, it is the proposal of the working group to develop the concept of the "cardio‐oncological evaluation," corresponding to a global and standardized cardiovascular assessment strategy to be proposed to patients with cancer who are referred to cardiologists, including risk factor assessment, ECG, biomarkers, and imaging evaluation (Table 2). This cardio‐oncological evaluation should be comprehensive before the initiation of cancer therapy in order to estimate the baseline risk of cardiovascular toxicity, but must be tailored to the anticancer drugs during follow‐up to avoid repeating unnecessary investigations. This is particularly relevant for lipid and glucose profiles, which should be monitored in patients treated with drugs that alter them (eg, Bcr‐Abl kinase inhibitors or mammalian target of rapamycin inhibitors).

Table 2

Cardiovascular Assessment Included in the “Cardio‐Oncological Evaluation”

Clinical consultation (including BP measurement) ECG Blood glucose,* lipid profile,* glomerular filtration rate calculation Cardiovascular global risk assessment using guidelines 17 , 18 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 LV contrast agents could be potentially useful in 2‐dimensional echochardiography CMR is recommended if the quality of TTE is suboptimal Use the same imaging modality for monitoring Actively manage modifiable cardiovascular risk factors and diseases Encourage exercise on a regular basis and healthy dietary habits

BP indicates blood pressure; CMR, cardiac magnetic resonance; DTI, Doppler tissue imaging; GLS, global longitudinal strain; LV, left ventricular; LVEF, left ventricular ejection fraction; and TTE, transthoracic echocardiogram.

All of these parameters should be measured during the first evaluation but will be rechecked during follow‐up only with cancer treatments that may modify them (eg, Bcr‐Abl inhibitors or mammalian target of rapamycin inhibitors).

Cardiovascular global risk assessment using guidelines ,

Anthracyclines

What do the Guidelines Say?

Anthracyclines are old drugs that have been associated with several cardiovascular toxicities, including left ventricular systolic dysfunction (LVSD) and heart failure (HF). , The monitoring strategies of anthracyclines proposed by the recent guidelines are shown in Table S2.

Briefly, all of the guidelines recommend screening and optimal management of cardiovascular diseases and risk factors before, during, and after anthracycline therapy. They emphasize the importance of screening for early signs of cardiotoxicity, allowing indication of cardioprotective strategies to prevent the development of overt LVSD and HF. However, there are many differences in the strategies for pretherapy assessment and monitoring (including the use of cardiac biomarkers such as troponin) as well as indications for drug prophylaxis in the primary prevention of cardiotoxicity. Regarding the long‐term follow‐up in survivors, no general agreement has emerged from these guidelines.

Which Pragmatic Approach May be Suggested?

The pragmatic harmonized approach proposed by the working group is depicted in Figure 1A.

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:

Clinical consultation (including BP measurement).

ECG.

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.

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.

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

CMR is recommended if the quality of TTE is suboptimal.

Use the same imaging modality for monitoring.

Actively manage modifiable cardiovascular risk factors and diseases.

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. ACEi 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.

In summary, anthracyclines should not be used in patients with LVEF <40% unless there is no effective alternative cancer treatment. In patients with LVEF <50% but ≥40% and those exposed to multiple cardiotoxic cancer treatments who have a normal LVEF and associated cardiovascular risk factors, anthracyclines can be used with a cardioprotective strategy using angiotensin‐converting enzyme inhibitors (ACEis) (or angiotensin receptor blockers [ARBs]) and/or β‐blockers (BBs). Regarding monitoring during therapy, the use of troponin to predict LVSD is highly variable according to the guidelines because of conflicting results in published studies. , , , , The working group proposed to use troponin in situations in which it has most clearly demonstrated its value, namely, high‐cumulative‐dose anthracycline (doxorubicin ≥250 mg/m2 or epirubicin ≥600 mg/m2), lower‐cumulative‐dose anthracycline in association with other cardiotoxic therapy, or cardiovascular risk factors. , , , , It is of importance that assays be performed by the same laboratory (same type of troponin, same method of measurement) and at the same time (within 24 hours after each infusion).

HER2 Inhibitors

HER2is (monoclonal antibodies: trastuzumab and pertuzumab; tyrosine kinase inhibitor: lapatinib) are associated with the occurrence of LVSD and HF. The monitoring strategies proposed by the current guidelines are shown in Table S3.

Briefly, all of the guidelines recommend a cardiological assessment before HER2i initiation, including a physical examination, ECG, and cardiac imaging, preferably transthoracic echocardiogram. However, there are important differences regarding initial and subsequent evaluation of cardiac biomarkers and pretherapeutic introduction of ACEis (or ARBs) and/or BBs in high‐risk patients. While most guidelines recommend cardiac imaging monitoring every 3 months during treatment, the ASCO‐2016 guidelines leave the choice of timing to the physician's discretion. No specific recommendations for HER2is are proposed by the guidelines regarding the long‐term follow‐up in survivors.

The pragmatic harmonized approach proposed by the working group is depicted in Figure 1B.

In summary, HER2is should not be used in patients with LVEF <40% unless there is no effective alternative cancer treatment. In patients with LVEF <50% but ≥40% and those exposed to multiple cardiotoxic cancer treatments with a normal LVEF and associated cardiovascular risk factors, HER2is can be used with a cardioprotective strategy using ACEis (or ARBs) and/or BBs. The working group proposes not only an imaging evaluation but also a complete cardio‐oncological evaluation every 3 months during HER2i treatment in all patients. The benefit of troponins to predict intravenous or subcutaneous HER2is cardiotoxicity is somewhat equivocal and appears to be more helpful, especially in patients with prior exposure to anthracyclines. Troponin evaluation may be used after each infusion in patients at higher risk of cardiotoxicity.

VEGF Inhibitors

VEGFis are associated with an increased risk of hypertension, myocardial ischemia, LVSD, QTc prolongation, and arterial thromboembolic events. The mammalian target of rapamycin inhibitors share similar potential cardiovascular adverse events (AEs) and can also cause hypercholesterolemia, hypertriglyceridemia, and hyperglycemia. The monitoring strategies proposed by the current guidelines are shown in Table S4.

Briefly, all of the guidelines recommend an initial cardiovascular evaluation including screening and management of cardiovascular risk factors, baseline blood pressure (BP) value, and LVEF measurement. During VEGFi therapy, the guidelines recommend the same general rules as for other cancer treatments with potential cardiotoxicity but highlight the importance of performing appropriate and close BP monitoring and screening of early signs and symptoms of HF. However, there is no consensus on the use of cardiac biomarkers or the timing of evaluations.

The pragmatic harmonized approach proposed by the working group is depicted in Figure 2A.

Figure 2

Pragmatic approach for monitoring patients treated with VEGFi and mTORis (A), Bcr‐Ablis (B), proteasome inhibitors (C), and ibrutinib (D).

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

Clinical consultation (including BP measurement).

ECG.

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 VEGFi, mTORi, and Bcr‐Abli.

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.

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

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

Use the same imaging modality for monitoring.

Actively manage modifiable cardiovascular risk factors and diseases.

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‐Abli 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; mTORi, mammalian target of rapamycin inhibitor; PAD, peripheral artery disease; TKi, tyrosine kinase inhibitor; and VEGFi, vascular endothelial growth factor inhibitor.

In summary, all patients eligible for VEGFi therapy should have a cardio‐oncological evaluation before treatment initiation because of the high frequency and rapid onset of cardiovascular AEs (a few days after VEGFi initiation). Then, the working group proposes to repeat it every 3 months the first year, then every 6 months during VEGFi therapy. Moreover, the patients should be educated on home BP monitoring. As the value of troponin in monitoring these molecules has not been demonstrated, its use is not recommended.

Bcr‐Abl Kinase Inhibitors

Bcr‐Abl kinase inhibitors (imatinib, dasatinib, nilotinib, bosutinib, and ponatinib) are associated with accelerated atherosclerosis, peripheral artery disease development, acute coronary syndrome, stroke, hypertension, hyperglycemia, hypercholesterolemia, pericardial effusion, pulmonary arterial hypertension, QTc prolongation, and occasionally LVSD. , , The monitoring strategies proposed by the current guidelines are shown in Table S4.

Briefly, despite this potential cardiovascular toxicity, none of the current guidelines specifically address Bcr‐Abl kinase inhibitor monitoring; they simply recommend the same general rules of monitoring as those for the other cancer treatments with potential cardiotoxicity.

The pragmatic harmonized approach proposed by the working group is shown in Figure 2B.

In summary, a monitoring strategy based on the specific risk of toxicity for each Bcr‐Abl kinase inhibitor drug and the individual global cardiovascular risk should be performed. Special attention should be paid to patients at very high or high individual cardiovascular risk (estimated by the current guidelines) , and those treated with nilotinib and ponatinib. Indeed, previously unrecognized and severe peripheral atherosclerosis has emerged as a critical concern with nilotinib, along with serious arterial thrombotic events with ponatinib. , , The results of several studies support the utilization of the ankle‐brachial index in this setting. An abnormal ankle‐brachial index (<0.9) is sensitive and specific for peripheral artery disease and could indicate systemic atherosclerotic disease. ,

Proteasome Inhibitors

Proteasomeis (carfilzomib, bortezomib, and ixazomib) are associated mainly with LVSD, HF, arterial hypertension, and myocardial ischemia. , The monitoring strategies proposed by the current guidelines are shown in Table S4.

Briefly, despite a cardiovascular toxicity profile clearly established with a high frequency of occurrence, none of the current guidelines specifically address proteasomei monitoring. They simply recommend the same general rules of monitoring as those for the other cancer treatments with potential cardiovascular toxicity.

The pragmatic harmonized approach proposed by the working group is depicted in Figure 2C.

In summary, all patients eligible for proteasomeis and particularly for carfilzomib should have a baseline cardio‐oncological evaluation before treatment begins. This initial evaluation should also contain a baseline measurement of natriuretic peptides and baseline home BP monitoring. This proposal is based on the fact that median time to first cardiovascular AE from proteasomeis start was 31 days, with 86% of cardiovascular events occurring within the first 3 months, and that baseline natriuretic peptides were also predictive of cardiovascular events. , After the baseline evaluation, it is suggested to repeat cardio‐oncological evaluation, including natriuretic peptides, and home BP monitoring every 3 months the first year, and every 6 months thereafter, throughout the course of proteasomei therapy.

Ibrutinib

Ibrutinib has been associated with atrial fibrillation (AF) since the early drug development phases. More recently, other cardiovascular toxicities were described, including hypertension, HF, ventricular arrhythmias, and conduction disorders.

Briefly, although the ibrutinib cardiovascular toxicity profile has been clearly established, especially the risk of AF, none of the current guidelines specifically address ibrutinib monitoring.

The pragmatic harmonized approach proposed by the working group is depicted in Figure 2D.

In summary, all patients eligible for ibrutinib therapy should have a baseline cardio‐oncological evaluation before treatment begins because of the multiple cardiovascular side effects associated with ibrutinib. , After the baseline evaluation, asymptomatic patients should receive repeat cardio‐oncological evaluation every 3 months the first year (and every 6 months afterward) associated with home BP monitoring during all ibrutinib therapy. The decision to perform cardio‐oncological evaluations every 3 months during the first year is based on the fact that conduction disorders mainly develop during the first 30 days and AF, ventricular arrhythmias, and HF have a peak incidence at 2 to 3 months, whereas hypertension occurs mainly after 4 to 5 months. Overall, cardiac AEs steadily occur during the first year after ibrutinib initiation. In symptomatic patients, we suggest adding repeated Holter‐ECG monitoring for AF screening.

Immune Checkpoint Inhibitors

ICis are associated with the occurrence of immune‐related myocarditis, which has a high mortality of ≈50%. , , , Pericarditis, supraventricular arrhythmias, acute coronary syndrome, and Takotsubo syndrome are other potential cardiovascular immune‐related AEs. , , The monitoring strategies proposed by the current guidelines are shown in Table S5.

Briefly, before ICi therapy, only the ASCO‐2018 recommend performing ECG and considering troponin, especially in patients treated with combination immune therapies but there is no consensus among the guidelines for either the pretherapeutic cardiovascular assessment or the monitoring of asymptomatic patients. The ASCO‐2018 and ESMO‐2020 guidelines recommend promptly performing an appropriate workup (ECG, troponin, B‐type natriuretic peptide or N‐terminal pro‐B‐type natriuretic peptide, C‐reactive protein, viral titer, echocardiogram with global longitudinal strain [GLS], and cardiac magnetic resonance) for patients who develop new cardiovascular symptoms or are incidentally noted to have arrhythmia or conduction abnormality on ECG or LVSD on echocardiogram while undergoing ICi therapy (or after recent completion).

The pragmatic harmonized approach proposed by the working group is depicted in Figure 3.

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.

In summary, it should be kept in mind that the clinical suspicion of ICi‐associated myocarditis is usually made by oncologists during patient monitoring. Hence, the proposed algorithm should be available in the oncology department, easy to perform, and easy for a noncardiologist to analyze. It is the proposal of the working group to consider 2 strategies that best reflect the entire possible clinical scenario. Strategy 1 considers baseline cardiovascular signs/symptoms, ECG, and troponin I or T for each patient deemed to receive ICi therapy. These parameters should be checked and compared with baseline values before each ICi administration and in case of noncardiovascular immune‐related AE occurrence. Strategy 2 considers that only cardiovascular signs/symptoms be checked before each ICi administration, and only patients with new cardiovascular signs/symptoms or noncardiovascular immune‐related AEs be evaluated with ECG and troponin. Strategies 1 and 2 consider that asymptomatic patients with a rise in troponin or new ECG abnormalities or patients with new cardiovascular signs/symptoms be rapidly referred to a cardio‐oncology unit able to confirm or deny the diagnosis of ICi‐related myocarditis.

Management of Cardiovascular Toxicity

LVSD and HF

Definitions and management of LVSD and HF proposed by the recent guidelines are shown in Table S6.

Briefly, several anticancer drugs have direct myocardial toxicity that can lead to LVSD and HF. Various terms are used according to the guidelines to define the different grades of myocardial involvement, such as “cancer treatment–related cardiac dysfunction,” “cardiac dysfunction,” “LVSD,” or “subclinical LVD.” The guidelines defined significant LVSD as a decrease in LVEF but with different cutoff values. While they agree with the recommendation to measure GLS with transthoracic echocardiogram and troponin for screening of early myocardial toxicity in some situations, the cutoff values also vary according to the guidelines as well as the indications for initiating cardioprotective therapy in these situations because of lack of strong evidence.

The pragmatic harmonized approach proposed by the working group is depicted in Figure 4.

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

Clinical consultation (including BP measurement).

ECG.

Blood glucose, lipid profile, glomerular filtration rate calculation.

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.

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

CMR is recommended if the quality of TTE is suboptimal.

Use the same imaging modality for monitoring.

Actively manage modifiable cardiovascular risk factors and diseases.

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 (ACEis) 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.

In summary, the following terms, definitions, and management of the different grades of left ventricular toxicity are proposed. “Overt cancer treatment–related LVSD” is defined as an LVEF drop of >10 percentage points to a value <50% or an LVEF drop of >20 percentage points. Its management is based on the presence of symptoms/signs of HF, LVEF value, and the type of cancer treatment. “Early cancer treatment–related myocardial toxicity” is defined as troponin level rise and/or GLS drop without overt myocardial toxicity. In accordance with all of the guidelines, troponin can be considered an early sign of myocardial toxicity if its level rises from baseline and exceeds the upper reference limit of the laboratory (same type of troponin, same method of measurement). Regarding the GLS cutoff value, the working group proposes to use the definition used by the ESMO‐2020 guidelines because it is the most sensitive, ie, an absolute GLS drop ≥5% or a relative drop ≥12%. Waiting for more results from ongoing randomized clinical trials, the initiation of ACEis (or ARBs) and/or BBs in these patients has been proposed.

Hypertension

The diagnostic criteria and management of cancer treatment–related hypertension proposed by the recent guidelines are shown in Table S7.

Briefly, although the guidelines differ in the definition of high BP and BP target, they agree on the need for early and aggressive pharmacological treatment in case of hypertension associated with a cancer treatment to prevent the development of cardiovascular complications. ACEis (or ARBs) and dihydropyridine calcium channel blockers are the preferred antihypertensive drugs in this situation, especially with VEGFi therapy. The nondihydropyridine calcium channel blockers (diltiazem and verapamil) should be avoided because of the risk of drug‐drug interactions. Discontinuation or dose reduction of cancer treatment may become necessary to control hypertension in a certain subset of patients not responding to any of the outlined measures. Once BP control is achieved, cancer treatment can be restarted to achieve maximum anticancer efficacy.

The pragmatic harmonized approach proposed by the working group is depicted in Figure 5A.

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

Clinical consultation (including BP measurement).

ECG.

Blood glucose, lipid profile, glomerular filtration rate calculation.

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.

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

CMR is recommended if the quality of TTE is suboptimal.

Use the same imaging modality for monitoring.

Actively manage modifiable cardiovascular risk factors and diseases.

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 () should be preferred to Bazett correction (). 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. ACEi 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.

In summary, high BP is defined as BP ≥140/90 mm Hg during the visit, measured with home BP monitoring ≥135/85 mm Hg or measured with 24‐hour Holter ≥135/85 mm Hg, which are the more accepted thresholds in current guidelines on hypertension and in line with expert statements. All patients experiencing new hypertension or worsening of preexisting hypertension associated with cancer treatment should benefit from a cardio‐oncology evaluation and the search for any proteinuria as well as the analysis of urine cytology. Unless there is presence of any hypertensive emergency or any hypertension‐mediated organ damage, the same cancer treatment should typically be continued, and an antihypertensive therapy must be quickly started or optimized. In cases of proteinuria >1 g/d, hematuria, or acute renal failure, patients must be referred to a nephrologist. When cancer treatment is interrupted, resumption can be discussed once hypertension is under control.

QTc Interval Prolongation

Only the ESC‐2016 guidelines provide recommendations regarding the management of QTc interval prolongation associated with cancer treatment (Table S8).

The pragmatic harmonized approach proposed by the working group is depicted in Figure 5B.

In summary, Fridericia correction should be preferred to Bazett correction, as it was also recommended by the E14 ICH guideline adopted by the Food and Drug Administration and European Medicines Agency in 2005. , This formula is more accurate , and may be preferable in the cancer population because there is less overcorrection and undercorrection in patients with tachycardia or bradycardia. If possible, manual QTc interval measurement is suggested using the recommended stepwise method. The QTc interval is prolonged when ≥450 ms in men and ≥460 ms in women. Cancer treatment can be continued as long as QTc interval is ≤500 ms and a change in QTc is <60 ms and there is no occurrence of any ventricular arrhythmias or syncope. Electrolyte abnormalities must be checked at each medical evaluation, as patients with cancer tend to be particularly at risk for developing hypokalemia (eg, caused by vomiting and diarrhea). Whenever possible, discontinuation of noncancer treatment drugs that induce QTc prolongation is warranted.

Atrial Fibrillation

Only the ESC‐2016 guidelines provide recommendations regarding the management of AF associated with cancer treatments (Table S9).

The pragmatic harmonized approach proposed by the working group is depicted in Figure 5C.

In summary, the initial approach to manage AF associated with cancer treatment has been chosen according to the 2 usual considerations, namely, the rhythm versus the rate‐control strategy and thromboembolic prophylaxis. , , Although no score has been validated to predict the thromboembolic and bleeding risk in the context of active cancer, the working group suggests to indicate anticoagulation according to a multiparametric evaluation including the CHA2DS2‐VASc score; thromboembolic and bleeding risk of the cancer; hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly (>65 years), drugs/alcohol (HAS‐BLED) score; platelet count; and life expectancy. It seems that lung, gastric, and pancreatic cancer are associated with a high risk of thromboembolic events. Low‐molecular‐weight heparin may be considered as a short‐term measure, while warfarin and direct oral anticoagulants may be considered as long‐term anticoagulation options. The choice should be based on the risk assessment of drug‐drug interactions of each anticoagulant with cancer treatments and the specific bleeding risk of each cancer. Regarding direct oral anticoagulants, Xa inhibitors may be preferred to IIa inhibitors. The uptake of all direct oral anticoagulants is influenced by the P‐glycoprotein system, but dabigatran appears to be the most at‐risk direct oral anticoagulants because of its low bioavailability and important renal elimination, which exposes it to a theoretical increased risk for drug levels outside of the therapeutic range. Regarding the decision on rate versus rhythm control, rate control rather than rhythm control strategy should be preferred, especially if the suspected cancer treatment causing AF is continued. , , BBs represent the first‐line pharmacological class because of no/few drug‐drug interactions with cancer treatments. Digoxin and nondihydropyridine calcium channel blockers (verapamil, diltiazem) must be avoided because of the high risk of drug‐drug interactions with cancer treatments (P‐glycoprotein system, cytochrome P450 system). , A rhythm control strategy can be discussed in patients who remain symptomatic despite rate control or in cases of hemodynamic instability. , However, the potential for drug‐drug and QTc interval prolongation must be considered when associating antiarrhythmic with anticancer drugs.

ICi‐Related Myocarditis

The diagnostic criteria and management of ICi‐related myocarditis proposed by the recent guidelines are shown in Table S10. Briefly, although the ASCO‐2018 and the ESMO‐2017 guidelines gave specific recommendations for the management of ICi‐related myocarditis, there is no consensus on diagnostic and therapeutic strategies in the absence of strong evidence. The diagnosis of ICi‐related myocarditis remains challenging, especially because patients with definite myocarditis on endomyocardial biopsy may have no signs of myocarditis on cardiac magnetic resonance in up to 50% of cases. Moreover, physicians are faced with the issue of asymptomatic patients with only a rise in troponin levels during their follow‐up. Regarding management, all available guidelines agree on the need to discontinue ICi therapy in patients with a suspected or proven ICi‐related myocarditis and to rapidly initiate high‐dose corticosteroids. For corticosteroid‐refractory or high‐grade myocarditis with hemodynamic instability, other immunosuppressive therapies such as antithymocyte globulin, infliximab (except in patients with HF), mycophenolate mofetil, or abatacept are suggested. However, their potential interest has not been demonstrated in prospective well‐designed trials.

The pragmatic harmonized approach proposed by our group is depicted in Figure 5D.

In summary, although they were developed to be used in clinical trials and have never been validated, the working group suggests using diagnostic criteria developed by Bonaca et al (Figure S1); however, they cannot replace clinical judgment. Moreover, it should be kept in mind that concomitant myositis may result in significant elevations of creatine kinase, creatine kinase isoforms, and even troponin T. In this scenario, troponin I would be the most specific option for myocardial injury, and creatine kinase‐MB should be used if troponin I is not available as recommended by other experts. Regarding management, halting ICi therapy and initiating high‐dose corticosteroids rapidly as soon as myocarditis is suspected is highly recommended. Intensification of immunosuppressive therapy should be discussed in case of unfavorable evolution. Recently, case reports have suggested the potential efficacy of abatacept, alemtuzumab, and tocilizumab associated or not with plasmapheresis. , Finally, we suggest that ICi therapy not be resumed even after recovery.

Conclusions

Cardiovascular monitoring and management of cancer therapy–related cardiovascular toxicity are key points that should be integrated into the course of each patient’s cancer treatment to improve its overall prognosis. However, the lack of strong supporting evidence does not allow a consensus between the international guidelines. Although the harmonized protocols proposed by the working group are not based on further evidence and do not consider all of the situations, they build on the most up‐to‐date version of each guideline and data from recent studies. These protocols provide practical easy‐to‐use algorithms to help clinicians make daily decisions. In therapeutic trials that test new anticancer drugs with potential cardiovascular AEs, cardio‐oncologists will have to apply the monitoring procedures specified in the prespecified research protocol. Nevertheless, if cardiovascular toxicity occurs, the algorithms proposed in the present statement might be helpful in management if the putative mechanisms are similar to those of the drugs addressed in this statement.

Further research in cardio‐oncology is needed to: (1) determine accurate and consensus‐based definitions of cardiovascular toxicity; (2) develop molecular approaches to better understand patient susceptibility; (3) develop cardiovascular strategies to screen for adverse effects, including the definition of high‐risk groups of patients and the monitoring that should be used; (4) develop clinical trials identifying the most effective treatments in cases of cardiovascular toxicity; and (5) recommend standardized long‐term cardiovascular monitoring in pediatric and adult cancer survivors.

Sources of Funding

This study received support from the Fédération Française de Cardiologie. The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the article; and decision to submit the article for publication.

Disclosures

Dr Thuny received modest fees for lectures outside the submitted work from Novartis, Merck Sharp and Dohme, Bristol‐Myers Squibb, Roche, and Astra‐Zeneca. Dr Cautela received modest lecture fees outside the submitted work from Merck Sharp and Dohme, Novartis, and Astra‐Zeneca. Dr Salem received modest fees for lectures outside the submitted work from Merck Sharp and Dohme, Bristol‐Myers Squibb, and Roche. Dr Cohen‐Solal received modest fees for lectures outside the submitted work from Novartis. Dr Barlesi received modest consultant fees outside the submitted work from Astra‐Zeneca, Bayer, Bristol‐Myers Squibb, Boehringer–Ingelheim, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Novartis, Merck, MSD, Pierre Fabre, Pfizer, and Takeda. Dr Ederhy received modest consultant and lecture fees outside the submitted work from Bristol‐Myers Squibb, Novartis, Celgene, EISAI, Astra‐Zeneca, and Janssen. Dr Mirabel received modest fees for lectures outside the submitted work from Astra‐Zeneca, Pfizer, Novartis, Roche, Sanofi, and Janssen. Dr Champiat reports outside the submitted work personal fees from Amgen, AstraZeneca, BMS, Fresenius Kabi, Janssen, MSD, Novartis, and Roche, other from As part of Gustave Roussy Drug Development Department (DITEP): principal/subinvestigator of Clinical Trials for Abbvie, Adaptimmune, Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen‐X Bvba, Arno Therapeutics, Astex Pharmaceuticals, Astra Zeneca, Astra Zeneca Ab, Aveo, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, Bioalliance Pharma, Biontech Ag, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Bristol‐Myers Squibb International Corporation, Ca, Celgene Corporation, Cephalon, Chugai Pharmaceutical Co., Clovis Oncology, Cullinan‐Apollo, Daiichi Sankyo, Debiopharm S.A., Eisai, Eisai Limited, Eli Lilly, Exelixis, Forma Tharapeutics, Gamamabs, Genentech, Gilead Sciences, Glaxosmithkline, Glenmark Pharmaceuticals, H3 Biomedicine, Hoffmann La Roche Ag, Incyte Corporation, Innate Pharma, Institut De Recherche Pierre Fabre, Iris Servier, Janssen Cilag, Janssen Research Foundation, Kura Oncology, Kyowa Kirin Pharm. Dev., Lilly France, Loxo Oncology, Lytix Biopharma As, Medimmune, Menarini Ricerche, Merck Kgaa, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Millennium Pharmaceuticals, Molecular Partners Ag, Nanobiotix, Nektar Therapeutics, Nerviano Medical Sciences, Novartis Pharma, Octimet Oncology Nv, Oncoethix, Oncomed, Oncopeptides, Onyx Therapeutics, Orion Pharma, Oryzon Genomics, Ose Pharma, Pfizer, Pharma Mar, Philogen S.P.A., Pierre Fabre Medicament, Plexxikon, Rigontec Gmbh, Roche, Sanofi Aventis, Sierra Oncology, Sotio A.S, Syros Pharmaceuticals, Taiho Pharma, Tesaro, Tioma Therapeutics, Wyeth Pharmaceuticals France, Xencor, Y's Therapeutics, grants from As part of Gustave Roussy Drug Development Department (DITEP): Research Grants from Astrazeneca, BMS, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi, non‐financial support from Astrazeneca, Bayer, BMS, Boringher Ingelheim, Johnson & Johnson, Lilly, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche. Dr Charbonnier reports personal fees from Incyte, personal fees from Pfizer, other from Novartis, outside the submitted work.

Tables S1–S10

Figure S1

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