JACC: CARDIOONCOLOGY VOL. 6, NO.

6, 2024

ª 2024 THE AUTHORS. PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN

COLLEGE OF CARDIOLOGY FOUNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDER

THE CC BY-NC-ND LICENSE (http://creativecommons.org/licenses/by-nc-nd/4.0/).

EXPERT PANEL

Cardiovascular Considerations
During Cancer Therapy
Gaps in Evidence and JACC: CardioOncology
Expert Panel Recommendations

Darryl P. Leong, MBBS, MPH, MBIOSTAT, PHD,a,b Sarah Waliany, MD, MS,c,d Husam Abdel-Qadir, MD, PHD,e
Katelyn M. Atkins, MD, PHD,f Tomas G. Neilan, MD, MPH,g Ninian N. Lang, MB CHB, PHD,h Jennifer E. Liu, MD,i
Anne H. Blaes, MD, MS,j Hira S. Mian, MD,k Heather N. Moore, PHARMD, BCOP, CPP,l Ludhmila A. Hajjar, MD,m
Alicia K. Morgans, MD, MPH,n Peter M. Ellis, MBBS, MMED, PHD,k Susan Dent, MDo

ABSTRACT

The administration of certain cancer therapies can be associated with the development of cardiovascular toxicity or com-
plications. This spectrum of toxicities is broad and requires nuanced approaches for prevention, identification, and man-
agement. This expert panel summarizes the consensus of opinions of diverse health care professionals in several key areas:
1) cardioprotection involves strategies aimed at the primary prevention of cancer therapy–related cardiovascular toxicity;
2) surveillance entails monitoring for cancer therapy–related cardiovascular toxicity during cancer therapy; 3) permissive
cardiotoxicity is the informed continuation of cancer therapy in the presence of cardiovascular toxicity, along with the
implementation of mitigating cardiovascular treatments; and 4) special considerations include the invasive management of
severe cardiovascular disease in patients receiving treatments for advanced cancer and the exploration of drug-drug
interactions in cardio-oncology. In this expert panel, we also highlight gaps in evidence in an effort to continue to advance
science in the cardiovascular care of our patients undergoing cancer therapy. (JACC CardioOncol. 2024;6:815–834)
© 2024 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

B etween 2010 and 2019, global cancer inci-

dence increased by 26%, with at least 17
million new cases reported in 2019 alone.1
This trend is expected to continue, with projections
suggesting a 53% increase in patients receiving first-
line chemotherapy from 2018 levels to 15 million by
2050. 2 Moreover, patients with cancer often undergo
additional treatments such as radiotherapy (RT),

From the aPopulation Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada;
b
Department of Medicine, McMaster University, Hamilton, Ontario, Canada; cMassachusetts General Hospital Cancer Center,
Boston, Massachusetts, USA; dDana-Farber Cancer Institute, Boston, Massachusetts, USA; eWomen’s College Hospital, Peter Munk
Cardiac Centre, University of Toronto, Toronto, Ontario, Canada; fDepartment of Radiation Oncology, Cedars-Sinai Medical
Center, Los Angeles, California, USA; gDivision of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston,
h
Massachusetts, USA; School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, United Kingdom;
i
Memorial Sloan Kettering Cancer Center, New York, New York, USA; jDivision of Hematology/Oncology, University of Minnesota,
Minneapolis, Minnesota, USA; kJuravinski Cancer Center, Department of Oncology, McMaster University, Hamilton, Ontario,
Canada; lDepartment of Pharmacy, Duke University Medical Center, Durham, North Carolina, USA; m
Cardio-Oncology Depart-
ment, InCor, Universidade de São Paolo, São Paolo, Brazil; nDepartment of Medical Oncology, Dana-Farber Cancer Institute,
Boston, Massachusetts, USA; and the oDuke Cancer Institute, Department of Medicine, Duke University, Durham, North Carolina,
USA.
Torbjørn Omland, MD, PhD, MPH, served as Guest Editor for this paper.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the Author Center.

Manuscript received September 7, 2023; revised manuscript received June 13, 2024, accepted June 27, 2024.

ISSN 2666-0873 https://doi.org/10.1016/j.jaccao.2024.06.005

816 Leong et al JACC: CARDIOONCOLOGY, VOL. 6, NO. 6, 2024

Managing Cardiotoxic Cancer Therapy DECEMBER 2024:815–834

ABBREVIATIONS immunotherapy, targeted therapies, and hor-

AND ACRONYMS HIGHLIGHTS
monal therapies, many of which are associ-
ated with adverse cardiovascular effects. 3

There is a need to prevent, detect and
5-FU = 5-fluorouracil
Consequently, there is an urgent need to manage CTR-CVT and CV events in cancer
ACEI = angiotensin-converting
develop strategies for the early identification patients.
enzyme inhibitor
and mitigation of cancer therapy–related car-
ADT = androgen deprivation
This panel provides recommendations to
therapy diovascular toxicity (CTR-CVT).
address this need based on current
ALKI = anaplastic lymphoma
These strategies may include the imple-
evidence.
kinase inhibitor mentation of evidence-based approaches to
ARB = angiotensin receptor prevent CTR-CVT (cardioprotection) and
Collaboration between oncology and
blocker surveillance strategies aimed at the early cardiology is key to optimize patient care.
CIED = cardiac implantable identification of CTR-CVT. When CTR-CVT is
electronic device
present, the risks and benefits of ongoing section, we review the potential cardioprotective
CML = chronic myeloid cancer therapy must be carefully considered. strategies on the basis of the respective cancer
leukemia
This decision involves discussions with the therapies.
CRS = cytokine release
patient, their caregivers, and treating health
syndrome ANTHRACYCLINES.
care providers. If the risk-benefit relationship
CTR-CVT = cancer therapy– Recommendations.
is favorable, a strategy of permissive CTR-
related cardiovascular toxicity
It is recommended to consider the use of
CYP = cytochrome P450
CVT may be adopted. This approach allows
angiotensin-converting enzyme inhibitors (ACEIs)
the continuation of cardiotoxic treatment
DDI = drug-drug interaction or angiotensin receptor blockers (ARBs) and/or
under close surveillance, accompanied by
DIBH = deep-inspiration breath beta-blockers in patients with breast cancer
hold appropriate cardiovascular therapies, with
undergoing anthracycline-based chemotherapy to
GnRH = gonadotropin
the goal of optimizing cancer treatment
prevent a decline in left ventricular ejection
hormone–releasing hormone delivery.4
fraction (LVEF). They are also recommended as the
HER2 = human epidermal Finally, given the higher risk for cardio-
antihypertensive agents of choice in patients with
growth factor receptor 2 vascular disease in patients with cancer
hypertension who require anthracycline treatment.
HF = heart failure compared with those without cancer, and the

The use of statins may be considered in patients
ICI = immune checkpoint increased likelihood of cancer in patients
with lymphoma treated with anthracycline to pre-
inhibitor with established cardiovascular disease,5
vent a decline in LVEF.
LV = left ventricle/ventricular specific management approaches for severe

For adults at high risk for heart failure (HF) and in
LVEF = left ventricular ejection cardiovascular disease in patients receiving
fraction
whom anthracycline is strongly indicated, dexra-
cancer therapy are essential.
zoxane or liposomal doxorubicin is recommended.
RT = radiotherapy The European Society of Cardiology has
TKI = tyrosine kinase inhibitor endorsed broad guidelines for cardio- Gaps in knowledge.
VEGFI = vascular endothelial oncology.6 Although most of these guidelines
It remains unclear whether ACEIs or ARBs, beta-
growth factor inhibitor blockers, or statins can prevent the development
are based on limited evidence and predomi-
nantly reflect expert opinion, the purpose of this pa- of HF in anthracycline recipients without left
per is to offer expert consensus recommendations ventricular (LV) dysfunction.
that are firmly supported by research. We also aim to
The specific patient population that would derive
highlight gaps in knowledge regarding CTR-CVT car- the greatest benefit from dexrazoxane or liposomal
dioprotection (Table 1), surveillance (Table 2), and doxorubicin has not been clearly defined.
permissive CTR-CVT (Table 3) in adults receiving
There is substantial interest in repurposing cardiac
cancer treatment (Central Illustration).
medications for the prevention of anthracycline-
related CTR-CVT. Some of these medications that
CARDIOPROTECTIVE STRATEGIES were relevant to baseline assessment (prior to cancer
therapy) were also discussed in the expert panel pa-
The management of cardiovascular risk factors in per by Raisi-Estabragh et al.7 We briefly review some
patients receiving potentially cardiotoxic cancer of these strategies in this statement, focusing on the
therapies should be optimized in accordance with time during therapy. Although neurohormonal
current the American College of Cardiology and blockade using a renin-angiotensin system antagonist
American Heart Association guidelines. In this or a beta-blocker may offer a small protective effect
JACC: CARDIOONCOLOGY, VOL. 6, NO. 6, 2024 Leong et al 817
DECEMBER 2024:815–834 Managing Cardiotoxic Cancer Therapy

T A B L E 1 Recommendations for Cardioprotection in Patients Receiving Cardiotoxic Cancer Therapies

Therapy Recommended Cardioprotective Strategy Gaps in Knowledge

Anthracycline
ACEIs/ARBs and/or beta-blockers should be considered in patients
It remains unclear whether ACEIs/ARBs, beta-blockers, and statins
with breast cancer undergoing anthracycline treatment to prevent reduce the risk of heart failure in patients with preserved systolic
LVEF decline. These are preferred antihypertensive agents for LV function receiving anthracycline therapy.
patients with hypertension indicated for anthracycline therapy.
The specific patient population that would benefit most from

Statin use should be considered in patients with lymphoma treated dexrazoxane or liposomal doxorubicin has not been clearly defined.
with anthracycline to prevent LVEF decline.

Dexrazoxane or liposomal doxorubicin should be considered for
adults at high risk for heart failure when anthracycline treatment is
strongly indicated.
HER2-targeted
ACEIs/ARBs and/or beta-blockers should be considered for
It remains unclear whether ACEIs/ARBs and beta-blockers reduce
therapies patients with breast cancer undergoing HER2-targeted therapies the risk of heart failure in patients with preserved systolic LV
to prevent LVEF decline. function receiving HER2-targeted therapies.
Radiotherapy
To minimize cardiac exposure to radiation, optimize patient posi-
Although emerging data support purposeful sparing of radiation
tioning, manage respiratory motion, and delineate target volumes. dose to specific cardiac substructures (eg, coronary arteries),
Advanced planning techniques and/or proton therapy should be optimal dose limits are not well established.
considered.

ACEI ¼ angiotensin-converting enzyme inhibitor; ARB ¼ angiotensin receptor blocker; HER2 ¼ human epidermal growth factor receptor 2; LV ¼ left ventricular; LVEF ¼ left ventricular ejection fraction.

on LVEF, there are no data demonstrating a reduction However, the reliability of these findings may be
in the incidence of clinical HF. 8-11 The primary pre- compromised by biases in one-half of the relevant
vention use of these medications must be carefully studies due to the absence of masking and possible
considered, weighing the potential beneficial effects incomplete outcome data.
against adverse effects. They may be most strongly Dexrazoxane is approved for use in women with
indicated in patients with hypertension and those metastatic breast cancer who have received 300 mg/m 2
with established indications for their use. doxorubicin and require ongoing anthracycline for
A randomized trial comparing atorvastatin 40 mg/d disease control. Nonetheless, the quality of evidence
with placebo in patients predominantly diagnosed supporting this use is considered low, and additional
with breast cancer receiving a median doxorubicin trials are recommended before its systematic imple-
dose of 240 mg/m 2 showed no difference in absolute mentation. 16 Although concerns have been raised
12
LVEF between the groups at 24 months. A more about an increased risk for subsequent cancers in
recent trial involving patients with lymphoma treated children treated with dexrazoxane, such associations
with a median dose of 300 mg/m 2 doxorubicin or have not been demonstrated in adults.17 Additionally,
equivalent showed that a lower proportion of patients dexrazoxane may cause myelosuppression, poten-
in the atorvastatin group experienced declines in tially leading to undesirable delays if chemotherapy
LVEF at 1 year when taking atorvastatin 40 mg/d vs needs to be withheld until recovery of white cell
those on placebo. 13 HF developed in 3% of the ator- counts. A meta-analysis of 2 randomized trials sug-
vastatin group and 6% of the placebo group gested a relative risk for grade 3 or 4 white cell count
(P ¼ 0.26). Another trial involving a heterogeneous abnormalities of 1.16 (95% CI: 1.05-1.29), 18 which could
group of patients with cancer treated with anthracy- potentiate hematologic toxicities from RT or
cline showed no post-treatment difference in LVEF chemotherapy.
between those atorvastatin 40 mg/d and those on Liposomal doxorubicin may serve as an alternative
placebo.14 On the basis of these findings, the use of for patients in whom anthracycline treatment is
atorvastatin 40 mg/d may be considered for patients warranted but who are at high risk for HF. The eval-
with lymphoma receiving anthracycline treatment. uation of HF risk prior to anthracycline administra-
Consistent data support the use of dexrazoxane in tion, as discussed in the expert panel paper by Raisi-
the primary prevention of anthracycline-related CTR- Estabragh et al,7 emphasizes strong risk factors such
2
CVT in patients who receive >250 mg/m doxorubicin as high cumulative doxorubicin doses ($300 mg/m 2
equivalent and those with pre-existing HF or reduced or equivalent) and pre-existing systolic LV dysfunc-
LVEF.10,15 Among patients with breast cancer tion. The pharmacokinetics of liposomal doxorubicin
receiving anthracycline, compared with control sub- are designed to alter drug tissue distribution,
jects, dexrazoxane reduces the occurrence of HF, reducing cardiac exposure while maintaining anti-
with a pooled RR of 0.19 (95% CI: 0.09-0.40). 16 tumor efficacy. A meta-analysis of 4 randomized trials
818 Leong et al JACC: CARDIOONCOLOGY, VOL. 6, NO. 6, 2024

Managing Cardiotoxic Cancer Therapy DECEMBER 2024:815–834

T A B L E 2 Recommendations in Cancer Therapy–Related Cardiovascular Toxicity Surveillance

Therapy Recommended Surveillance Gaps in Knowledge

Anthracycline
Echocardiography The yield and ideal frequency of surveillance tests are uncertain, and it is
B Recommended routinely at baseline. unknown whether cardiovascular interventions predicated on these
B Should be considered during follow-up only based on tests improve clinical outcomes.
clinical features or for those at high risk. a
HER2-targeted
Adjuvant or neoadjuvant therapy: measure LVEF every 3 mo, It is uncertain whether less frequent surveillance or the use of blood
therapy preferably by echocardiography. biomarkers can effectively identify those at risk for heart failure.

Metastatic setting: measure LVEF every 6 months.

Echocardiography: preferred method for measuring LVEF.
ADT
Cardiovascular symptoms, established cardiovascular disease,
The optimal strategy to minimize the risk of adverse cardiovascular
smoking, blood pressure, and weight should be recorded at outcomes in ADT recipients is not well established.
baseline for all recipients.
The generalizability of cardiovascular risk scores developed for the

Primary care physicians should be made aware of the cardiometabolic general population to patients with prostate cancer remains
adverse effects of ADT to optimize cardiovascular risk factor unknown.
management.

It is reasonable to refer patients receiving ADT who do not regularly
see a cardiologist or internist to one if they have cardiovascular
symptoms, established cardiovascular disease (including incidental
arterial calcification on diagnostic imaging), or blood pressure
>140/90 mm Hg.
VEGFIs
Blood pressure: monitor frequently during the first cycle of Optimal approach to identify those who will develop LV dysfunction
treatment and after any dose changes; subsequently, related to VEGFI use.
every 2-3 wk.

Perform baseline TTE in all patients. Repeat TTE may be considered
6-8 wk after starting treatment in high-risk patients.
Bruton tyrosine
Check blood pressure and heart rate with or without ECG at each Frequency and intensity of cardiac rhythm monitoring strategies.
kinase clinic visit in all recipients of ibrutinib.
inhibitors
ALKIs
Check heart rate and blood pressure at baseline and at
Optimal frequency of lipid surveillance in patients receiving
subsequent clinic visits. lorlatinib.

Lorlatinib: check lipid levels at baseline, then with each cycle
The optimal management of patients who develop severe
of therapy until lipids are stable, followed by every 3 mo. bradycardia on ALKIs has not been defined.
Osimertinib
Recommend conducting baseline ECG and echocardiography.
The role of echocardiographic surveillance remains uncertain.

Avoid QT interval–prolonging drugs and electrolyte abnormalities.
The optimal dosing of osimertinib and corrected QT intervals in

Consider monitoring the QT interval and, for those at high risk, patients who exhibit QT interval prolongation remain unknown.
conducting echocardiographic surveillance.
ICIs
Conduct troponin and ECG at baseline.
A surveillance strategy for myocarditis with acceptable sensitivity

Most patients with suspected ICI myocarditis should be hospitalized. and specificity for clinical use has not been defined.
For patients diagnosed with ICI myocarditis or those with suspected
The optimal adjunctive therapy to high-dose corticosteroids for
ICI myocarditis presenting with major cardiac events, initiate the treatment of ICI myocarditis is uncertain.
high-dose corticosteroids rapidly.

a
High risk is conferred by prior therapies and cardiovascular risk factors as described in the text.
ADT ¼ androgen-deprivation therapy; ALKI ¼ anaplastic lymphoma kinase inhibitor; ECG ¼ electrocardiography; ICI ¼ immune checkpoint inhibitor; TTE ¼ transthoracic echocardiography; VEGFI ¼ vascular
endothelial growth factor inhibitor; other abbreviations as in Table 1.

demonstrated that liposomal doxorubicin signifi- LVEFs <50% (4.6% vs 15.8%).20 However, another
cantly reduces the risk for HF compared with doxo- randomized trial involving 90 treatment-naive
rubicin, with a pooled OR of 0.18 (95% CI: 0.08- patients $60 years of age with diffuse large B cell
0.38).15 lymphoma and baseline LVEFs $55% showed no
In contrast, a more recent systematic review, benefit on LVEF. 21
focusing exclusively on grade 3 adverse cardiovas-
HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR
cular events, did not show a statistically significant
2–TARGETED THERAPIES.
advantage to using liposomal doxorubicin, with a
Recommendations.
pooled OR of 0.60 (95% CI: 0.34-1.07).19 Notably, both

It is recommended to consider the use of ACEIs or
systematic reviews found limited evidence in the
ARBs and/or beta-blockers in patients with breast
lymphoma population. A more recent randomized
cancer undergoing human epidermal growth
trial involving 88 treatment-naive patients with
factor receptor 2 (HER2)–targeted therapies to
diffuse large B cell lymphoma, who lacked cardio-
prevent a decline in LVEF.
vascular risk factors, demonstrated that substituting
nonpegylated liposomal doxorubicin for doxorubicin Gaps in knowledge.
in the R-CHOP (rituximab, cyclophosphamide, doxo-
It remains unclear whether ACEIs or ARBs and/or
rubicin hydrochloride, vincristine sulfate, and pred- beta-blockers can prevent HF in patients with breast
nisone) regimen resulted in fewer individuals with cancer treated with HER2-targeted therapies.
JACC: CARDIOONCOLOGY, VOL. 6, NO. 6, 2024 Leong et al 819
DECEMBER 2024:815–834 Managing Cardiotoxic Cancer Therapy

T A B L E 3 Recommendations in Permissive Cardiotoxicity

Therapy Recommended Strategy Gaps in Knowledge

Anthracycline
The risks and benefits of continuing anthracycline in patients
The acute and long-term risk for heart failure in patients with LV
with LV dysfunction should be evaluated by a multidisciplinary team, dysfunction treated with anthracycline, including liposomal
considering the use of dexrazoxane, liposomal doxorubicin, and doxorubicin, are unknown.
alternative cancer treatments.
HER2-targeted
HER2-targeted therapy may continue in patients with mild, The benefits of continuing HER2-targeted therapy in patients with mild
therapy minimally symptomatic LV dysfunction, but there is a 5%-10% LV dysfunction are poorly defined.
incidence of heart failure.
5-fluorouracil,
Consider nitrates and/or calcium channel blockers if rechallenging The risk for recurrent coronary vasospasm on rechallenge with
capecitabine with 5-fluorouracil/capecitabine after suspected coronary vasospasm, 5-fluorouracil or capecitabine is unknown.
but ensure that the setting is closely monitored.
Other cancer
Decision making should be individualized, understanding the The risks and benefits of permissive cardiotoxicity for other cancer
therapies patient’s goals of care and involving cancer specialists and therapies have not been systematically studied.
cardiologists.

Abbreviations as in Table 1.

In a systematic review of trials comparing ACEIs or proved effective in reducing the dose to the heart and
ARBs or beta-blockers with placebo in patients with the left anterior descending coronary artery during
breast cancer undergoing trastuzumab-based ther- treatment for left-sided breast cancer, compared with
apy, these medications led to a modest attenuation of free-breathing treatment. Interestingly, patients with
LVEF decline. 11 Among 1,362 participants in 9 ran- right-sided disease may also benefit from DIBH,
domized trials, individuals allocated to receiving particularly when treated with regional nodal
ACEIs or ARBs or beta-blockers had a pooled mean irradiation.22 Additionally, DIBH has demonstrated
LVEF that was 2.3% (95% CI: 0.0%-4.6%) higher than cardiac dosimetric advantages in the treatment of
those in the control group. However, the follow-up gastric lymphoma.23
duration in these studies was short, and it is not Prone positioning. Prone positioning uses gravity to
clear if this small difference in LVEF confers a clinical pull the breast away from the chest wall, which allows
benefit. In addition, most of these trials were not more shallow tangent beams and consistently re-
blinded, and the risk for bias was considered high. duces the ipsilateral lung dose across different later-
Currently, no data are available on the use of ACEIs or ality. However, this prone positioning may cause the
ARBs or beta-blockers to prevent LVEF decline in heart to move anteriorly toward the chest wall. Data
patients treated with dual HER2 blockade (eg, tras- on whether this results in consistently higher or lower
tuzumab and pertuzumab) or antibody-drug conju- cardiac doses are mixed, particularly compared with
gates (eg, trastuzumab emtansine). supine DIBH.
RADIATION THERAPY. Tumor motion management, margin shrinkage, and
Recommendations. target volume reduction. Additional strategies to

It is recommended to prioritize the optimization of optimize RT planning include the reduction of plan-
patient positioning, management of respiratory ning target volume. This can be achieved by mini-
motion, and target volume delineation to minimize mizing or accounting for tumor motion amplitude
cardiac exposure to radiation. Additionally, using 4-dimensional computed tomography, breath
consideration for advanced planning techniques hold, forced shallow breathing through abdominal
and/or proton therapy is advised. compression, real-time tumor tracking and/or
gating, adaptive RT techniques, and/or daily image
Gaps in knowledge.
guidance. Respiratory gating techniques use a

Although emerging data support the purposeful
monitoring system to deliver RT during specific
sparing of radiation dose to specific cardiac sub-
phases of the respiratory cycle, whereas motion-
structures (eg, coronary arteries), optimal dose
encompassing techniques generate a target volume
limits have not been well established.
that includes the tumor’s location at any point
R e d u c i n g c a r d i a c d o s e e x p o s u r e . Deep-inspiration during the respiratory cycle.
breath hold. Deep-inspiration breath hold (DIBH) le- A d v a n c e d R T p l a n n i n g t e c h n i q u e s . Photon RT.
verages the natural physiology of the respiratory cy- Modern photon techniques, such as inverse planned
cle to distance the heart from the chest wall or breast, intensity-modulated RT or volumetric modulated
thereby minimizing cardiac dose exposure. DIBH has arc therapy, optimize high-dose conformality and
820 Leong et al JACC: CARDIOONCOLOGY, VOL. 6, NO. 6, 2024

Managing Cardiotoxic Cancer Therapy DECEMBER 2024:815–834

C E N T R A L IL L U ST R A T I O N Recommendations for Cardioprotection, Surveillance for Cancer

Therapy–Related Cardiovascular Toxicity, and Permissive Cardiotoxicity

Leong DP, et al. JACC CardioOncol. 2024;6(6):815–834.

This figure illustrates the comprehensive approach to cardio-oncology care during the administration of potentially cardiotoxic cancer
therapies, adhering to evidence-based recommendations from the expert panel. Cardioprotection includes strategies to minimize cardio-
vascular toxicity from cancer treatments. Surveillance involves ongoing monitoring strategies during therapy. Permissive cardiotoxicity refers
to the management strategies that allow the continuation of cancer treatments known to cause cardiovascular effects. 5-FU ¼ 5-
fluorouracil; ACEI ¼ angiotensin-converting enzyme inhibitor; ALKi ¼ anaplastic lymphoma kinase inhibitor; ARB ¼ angiotensin receptor
blockers; BTKi ¼ Bruton tyrosine kinase inhibitor; ECG ¼ electrocardiography; HER-2 ¼ human epidermal growth factor receptor 2;
ICI ¼ immune checkpoint inhibitor; LV ¼ left ventricular; LVEF ¼ left ventricular ejection fraction; VEGFi ¼ vascular endothelial growth factor
inhibitor.

aid organ-at-risk sparing, superior to traditional Proton radiation therapy. Proton RT, which uses
3-dimensional conformal RT. However, these particle radiation, eliminates exit dose, thus mini-
advances come at the expense of increased low-dose mizing low-dose bath. In breast cancer, intensity-
scatter. For breast RT, the benefits of these modulated proton therapy may provide significant
techniques are observed primarily in cases of cardiac dosimetric advantages over photon-based
challenging anatomy, such as synchronous bilateral methods, especially in scenarios involving regional
breast cancer or regional nodal irradiation. For nodal irradiation or bilateral breast cancer,
locally advanced lung and esophageal cancers, these particularly beneficial for younger patients facing
approaches consistently improve cardiopulmonary the highest lifetime cumulative toxicity risks.
dosimetry and are associated with improved Similarly, for locally advanced lung and esophageal
survival outcomes in retrospective analyses. 24 cancers, intensity-modulated proton therapy has
JACC: CARDIOONCOLOGY, VOL. 6, NO. 6, 2024 Leong et al 821
DECEMBER 2024:815–834 Managing Cardiotoxic Cancer Therapy

shown promise in improving cardiopulmonary dose evidence to support CTR-CVT surveillance in most
sparing and reducing the overall total toxicity settings is limited.
burden, 25 though it remains investigational. It is ANTHRACYCLINES.
important to note, however, that the availability of Recommendations.
proton RT resources is limited given their
It is reasonable to perform surveillance echocardi-
substantial capital and operational costs. ography during anthracycline therapy to detect
Cardiac implantable electronic devices. Ionizing radi- declines in LVEF in select asymptomatic high-
ation can damage cardiac implantable electronic risk individuals.
devices (CIEDs), making multidisciplinary communi-
cation among radiation oncology, cardiology, and/or Gaps in knowledge.
electrophysiology essential to ensure effective and
The benefits and optimal timing of routine echo-
safe RT. Damage to CIEDs during RT may result cardiography or blood biomarker surveillance for
from electromagnetic interference, cumulative dose anthracycline CTR-CVT have not been consistently
effects, and secondary neutron production. demonstrated.
Risk assessment. RT damage to implantable
Anthracyclines continue to be a cornerstone of
cardioverter-defibrillators can lead to oversensing and
chemotherapy for various malignancies, including
inappropriate shocks. The total (maximum) absorbed
lymphoma, acute myeloid leukemia, sarcoma, and
dose should be minimized, with a goal of #5 Gy and
some breast cancers.32,33 The associated risk for CTR-
ideally <2 Gy, which is typically achievable with an
CVT, namely, LV dysfunction and HF, is dose
RT field positioned more than 5 cm from the
26,27 dependent, though instances of HF at low doses have
CIED. Secondary neutron contamination, which
been reported.34 The highest risk for HF occurs in
can occur independently of the absorbed dose or
individuals receiving >250 mg/m 2 doxorubicin or
distance from the CIED, is produced when protons,
>600 mg/m 2 epirubicin.19 This risk is also heightened
high-energy photons (>10 MV) or electrons (>20
for those receiving moderate doses in conjunction
MeV) interact with material in the treatment device
with chest irradiation that includes the heart, as well
head.
as those with pre-existing cardiovascular risk factors,
Risk-based management. Risk classification schemes
28,29 age >60 years, borderline or decreased LVEFs, and
have been described. High-risk individuals, such
histories of cardiovascular disease. The risk associ-
as those receiving a cumulative dose of >5 Gy, may
ated with lower doses of anthracyclines (#250 mg/m 2
require risk mitigation strategies. These strategies
doxorubicin) is less pronounced in the absence of
include high neutron contamination, pacer de-
cardiac risk factors.
pendency, or the presence of an implantable
cardioverter-defibrillator. Risk management may E c h o c a r d i o g r a p h y . It is generally recommended
involve considering CIED relocation and conducting to perform baseline echocardiography before expo-
CIED interrogations before RT, weekly during RT, and sure to anthracyclines, ideally incorporating
1 and 6 months after RT. Additionally, measures such 3-dimensional LVEF 35 and global longitudinal
as pulse oximetry, heart monitoring, access to strain,36 to establish a baseline measurement in case
external pacing, and magnet use should be consid- of subsequent cancer therapy–related LV dysfunc-
ered in consultation with electrophysiologists. tion. Echocardiography, preferred for its lack of
ionizing radiation, greater accessibility, and lower
CTR-CVT SURVEILLANCE DURING cost compared with alternative imaging modalities, is
CANCER THERAPY explored in more detail in the expert panel paper by
Raisi-Estabragh et al. 7
Surveillance for CTR-CVT during cancer treatment During anthracycline therapy, LVEF typically de-
may be considered when the: 1) toxicity can be creases by approximately 3%.37 However, the corre-
reliably detected at the time of the treatment; 2) the lation between such a decrease and the subsequent
specific CTR-CVT is important in that it is common development of HF remains understudied. In a pro-
or potentially serious and is actionable; and 3) the spective cohort study involving 2,625 patients
cost of surveillance is acceptable. 30,31 We discuss receiving moderate doses of anthracyclines, with
the role of CTR-CVT surveillance across major clas- echocardiography conducted every 3 months, 226
ses of cancer therapy on the basis of these princi- (9%) developed CTR-CVT, defined as a reduction in
ples (Table 2). Notably, with few exceptions, LVEF of more than 10% from baseline to an absolute
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Managing Cardiotoxic Cancer Therapy DECEMBER 2024:815–834

value <50%.38 Among these 226 individuals, 15 (7%) identify decreased LVEF, whereas in others, they are
experienced cardiac death or HF, all of whom had evaluated as predictors of future LVEF deterioration.
been prescribed ACEIs and/or beta-blockers. The Given these limitations, along with the high fre-
effectiveness of these medications in reducing the quency of cardiac troponin elevation after anthracy-
risk for cardiac death or HF in this population, as well cline exposure and the modest positive predictive
as the cost-effectiveness of this strategy, remains value of this test, routine surveillance of cardiac
unproven. Therefore, routine measurement of LVEF troponin during anthracycline administration may
during anthracycline administration is not recom- not be an efficient way to improve clinical outcomes.
mended except for research purposes. However, it However, measuring cardiac troponin at baseline
may be reasonable to monitor cardiac function in to provide a benchmark is considered reasonable.
select high-risk individuals, including those with In comparison, data on the predictive ability of
hypertension, diabetes, obesity, 39 or established natriuretic peptide levels for CTR-CVT are sparse.
structural or functional heart disease, as well as in- Currently, there is insufficient evidence to recom-
dividuals at the extremes of age or receiving high mend routine measurement of natriuretic peptides
doses of anthracycline (>250 mg/m 2 doxorubicin or during anthracycline therapy.
equivalent). HER2-TARGETED THERAPIES.
Global longitudinal strain is regarded as a more Recommendations.
sensitive marker of CTR-CVT than LVEF. A decline in
LVEF should be measured every 3 to 4 months
global longitudinal strain (>15% relative change) may during therapy for early-stage cancer.
prompt the initiation of cardioprotective medica-
It is reasonable to consider measurement of LVEF
tions. However, the initiation of therapy on the basis every 6 months during therapy for metastatic dis-
of global longitudinal strain measurements has not ease or as clinically indicated.
been proved to prevent reductions in LVEF at 1 year 40
Echocardiography is the preferred method modal-
or 3 years.41 ity for measuring LVEF.
B l o o d b i o m a r k e r s . A systematic review evaluated
Gaps in knowledge.
the relationship between elevated levels of cardiac

It is not known whether it is safe to monitor LVEF
troponin or natriuretic peptides (defined according to
42 less frequently in specific groups of HER2-targeted
the reference values of each study) and CTR-CVT.
therapy recipients.
Among 2,163 patients who had cardiac troponin
measured after exposure to cancer treatments, often Overexpression of HER2 occurs in 10% to 30% of
including anthracycline, 22% had elevated cardiac primary invasive breast cancers,44,45 as well as in
troponin levels. This elevation was associated with several gastrointestinal and genitourinary malig-
higher odds of impaired LVEF, with an OR of 12 nancies, and is associated with more aggressive dis-
(95% CI: 4-32). Additionally, elevated cardiac ease. HER2-targeted therapy, when combined with
troponin had a positive predictive value of 52% and a chemotherapy, improves survival rates in breast
negative predictive value of 93% for LV dysfunction, cancer, metastatic gastric cancer, and gastroesopha-
which occurred in 17% of patients. However, the re- geal junction adenocarcinoma that overexpress
view did not provide information on the association HER2. Dual HER2-targeted therapy (eg, trastuzumab
between elevated cardiac troponin levels and the risk and pertuzumab) combined with chemotherapy has
for HF or cardiovascular death, nor did it differentiate been shown to improve clinical outcomes in patients
results by the generation of cardiac troponin assay with breast cancer across neoadjuvant, adjuvant, and
used. A more recent study demonstrates that advanced settings. Furthermore, HER2 antibody-drug
measuring cardiac troponin during anthracycline- conjugates, such as trastuzumab emtansine and
based therapy does not effectively predict which pa- trastuzumab deruxtecan, are used in patients with
tients will develop reduced LVEF.43 residual breast cancer after neoadjuvant therapy and
The adoption of high-sensitivity assays is expected in advanced settings. HER2-targeted tyrosine kinase
to increase the rate of troponin positivity, leading to inhibitors (TKIs), such as lapatinib and tucatinib, are
workflow challenges and the identification of in- approved for use in advanced breast cancer after
dividuals with minor myocardial injuries whose sig- progression following an antibody-drug treatment.
nificance is unclear. Moreover, there is heterogeneity Furthermore, the combination of trastuzumab and
in the timing of blood tests and a conflation of tucatinib has been approved for treating advanced
biomarker measurements concurrent with LVEF renin-angiotensin system wild-type colorectal cancer
assessments. In some instances, biomarkers may from the second line of treatment onward.
JACC: CARDIOONCOLOGY, VOL. 6, NO. 6, 2024 Leong et al 823
DECEMBER 2024:815–834 Managing Cardiotoxic Cancer Therapy

Trastuzumab-related CTR-CVT manifests as LV high-risk biochemical recurrence after definitive

dysfunction in 15% to 20% of recipients and less prostate cancer therapy. It is prescribed for nearly
frequently as HF in 3% to 4%. These complications one-half of all patients with prostate cancer during
are seen primarily in patients who have also received the disease course. 47
anthracyclines. A systematic review indicates that ADT leads to an increased burden of cardiovascular
dual HER2-targeted therapy (eg, trastuzumab and risk factors such as weight gain, hypertension, dia-
pertuzumab) may increase the risk for clinical HF betes, and sarcopenia, potentially increasing the risk
compared with single-agent trastuzumab, with a for cardiovascular disease.48,49 Consequently, sur-
46
pooled relative risk of 1.97 (95% CI: 1.05-3.71). The veillance for cardiovascular risk factors in ADT re-
incidence of CTR-CVT reported in clinical trials for cipients is generally advocated. However, these risk
antibody-drug conjugates and HER2 TKIs has been factors are poorly managed in many individuals un-
relatively low (0.4%-7%). However, this finding is dergoing ADT, highlighting a significant treatment
based on short-term follow-up and may result partly gap.50,51 This gap is difficult to bridge because the
from the exclusion of patients who previously management of cardiovascular risks typically falls
developed CTR-CVT from other HER2-targeted ther- outside the scope of expertise of many prostate can-
apies, suggesting that those treated with newer cer physicians, and current strategies for managing
agents may be self-selected as less susceptible to these risks are generally inadequate.
HER2-associated CTR-CVT. Efforts to bridge this treatment gap include pro-
In registration trials in which regular surveillance posed strategies that involve engaging with primary
of LVEF was required per protocol, few patients care physicians and cardiologists. These strategies,
developed clinical HF. LVEF was measured approxi- among other approaches, are currently under inves-
mately every 3 months in these trials. In line with tigation. Until more definitive data are available, it is
these protocols, we recommend assessing LVEF every reasonable for physicians who prescribe ADT to
3 to 4 months during HER2-targeted therapy. How- screen for established cardiovascular diseases, car-
ever, for patients with metastatic disease, in whom diovascular symptoms, hypertension, and obesity.
the threshold for discontinuing HER2-targeted ther- They should also discuss smoking cessation and the
apy in the presence of asymptomatic LV dysfunction benefits of diet and exercise. Furthermore, diagnostic
may be higher, less frequent LVEF monitoring may be imaging often used in this patient population may
reasonable. In this group, decision making should be incidentally reveal arterial calcification, a finding that
individualized, considering factors such as the dura- doubles the risk for adverse cardiovascular events
tion of treatment, alternative therapies, disease compared with its absence.52
extent, and patient preferences. Although there is evidence to hypothesize that
GnRH antagonists may be associated with lower car-
ANDROGEN DEPRIVATION THERAPY. diovascular risk compared with GnRH agonists,53 the
Recommendations. quality of this evidence is insufficient to recommend

It is reasonable for patients receiving androgen GnRH antagonists for reducing cardiovascular risks.
deprivation therapy (ADT) to consult a cardiologist
if they experience cardiovascular symptoms, have OTHER THERAPIES THAT CAN AFFECT
cardiovascular disease (which may include arterial CARDIOVASCULAR RISK FACTORS,
calcification incidentally identified on diagnostic CARDIAC FUNCTION, OR RHYTHM
imaging), or have blood pressure > 140/90 mm Hg.
VASCULAR ENDOTHELIAL GROWTH FACTOR
Gaps in knowledge.
INHIBITORS.

The generalizability of cardiovascular risk scores,
Recommendations.
originally developed for the general populations,

Daily home blood pressure monitoring is recom-
to patients with prostate cancer is unknown.
mended during the first cycle of vascular endo-

There is no clearly defined optimal strategy
thelial growth factor inhibitor (VEGFI) treatment
to minimizing cardiovascular risk in patients
and after any change in VEGFI dose. After this
receiving ADT, including the role of gonadotropin
initial period, monitoring should be performed at
hormone–releasing hormone (GnRH) antagonists.
regular intervals, such as every 2 to 3 weeks.
ADT significantly prolongs survival across multiple
Baseline echocardiography is recommended for all
disease states in prostate cancer, including metastatic recipients beginning VEGFI therapy. For high-risk
prostate cancer, as adjuvant therapy with RT for individuals, consider follow-up echocardiography
localized prostate cancer, and for patients with 8 weeks after the initiation of VEGFIs.
824 Leong et al JACC: CARDIOONCOLOGY, VOL. 6, NO. 6, 2024

Managing Cardiotoxic Cancer Therapy DECEMBER 2024:815–834

Gaps in knowledge. Gaps in knowledge.

The benefits and optimal timing of routine echo-
The role of screening for peripheral arterial disease
cardiogram surveillance for CTR-CVT in unselected by ankle-brachial index or imaging in patients
patients receiving VEGFIs remain unproven. treated with TKIs for CML remains uncertain.

VEGFIs are used in treatment for various malig- TKIs used in the treatment of CML are associated
nancies, including renal, thyroid, and colorectal with the development of pericardial effusions. Post
cancers, sarcomas, neuroendocrine tumors, and hoc analyses of randomized trials suggest that sec-
gastrointestinal stromal tumors. Because VEGFIs ond- and third-generation TKIs, compared with ima-
function primarily by inhibiting the growth of tu- tinib, may increase the risk for vascular occlusive
mor blood vessels, they can also interfere with adverse events.59 Notably, with nilotinib, rates of
cardiovascular homeostasis. Notably, up to 80% of myocardial infarction, cerebrovascular disease, or
patients treated with VEGFIs develop hyperten- peripheral arterial disease requiring hospitalization
sion,54 which can be severe. Consequently, it is are reported at 31 (17-45) per 1,000 person-years. 60
recommended to monitor blood pressure at home Similarly, ponatinib has been linked to serious
daily during the first cycle of treatment and after adverse cardiovascular, cerebrovascular, and periph-
any change in VEGFI dose. After this period, eral vascular events, observed in 5.1%, 2.4%, and
monitoring should be continued every 2 to 3 weeks. 2.0% of patients, respectively, over a median of
Blood pressure targets and treatment thresholds 15 months. 61 Additionally, dasatinib is specifically
vary depending on the clinical context and cancer implicated in the occurrence of precapillary pulmo-
prognosis. The treatment of VEGFI-associated hy- nary hypertension 62 and pleural effusions in the
pertension typically involves the use of standard absence of pulmonary hypertension. Both nilotinib
agents; however, verapamil and diltiazem are and dasatinib are associated with QT interval
generally avoided because of their potential for cy- prolongation.63
tochrome P450 (CYP) 3A4 drug-drug interactions Data to inform surveillance strategies for cardio-
(DDIs) with VEGFIs. 54 vascular complications associated with TKI therapy in
LV dysfunction is observed in 10% to 28% of CML are limited. It may be reasonable to perform
patients treated with VEGFIs.55,56 Although hyper- baseline echocardiography before starting dasatinib
tension and elevated LV afterload may contribute to to evaluate pulmonary arterial pressure when feasible
LV dysfunction, direct cardiomyocyte toxicity and and electrocardiography to measure the corrected QT
coronary microvascular dysfunction are also impli- interval before initiating nilotinib treatment. How-
cated.57 VEGFI-associated LV dysfunction may be ever, the value of surveillance of asymptomatic in-
reversible; therefore, prompt recognition and treat- dividuals for cardiovascular complications during
ment are vital to avoid symptomatic HF and to CML treatment remains uncertain.
maximize the potential to continue or resume the BRUTON TKIs.
safe administration of VEGFIs. Given the poorly Recommendations.
defined risk factors for VEGFI-associated LV
Blood pressure and heart rate, with or without
dysfunction, we recommend performing baseline electrocardiography, should be checked at each
echocardiography in all patients starting VEGFI clinic visit for all recipients of Bruton TKIs.
therapy. Furthermore, for those at higher risk,
echocardiography is advised 6 to 8 weeks after Gaps in knowledge.
starting treatment, as cardiotoxic effects associated
The role of ambulatory heart rhythm monitoring in
with VEGFIs are frequently observed early. 55,58 Bruton TKI recipients is uncertain.

TKIs FOR CHRONIC MYELOID LEUKEMIA. Bruton TKIs are used in treating chronic lympho-
Recommendations. cytic leukemia, Waldenstrom macroglobulinemia,

Echocardiography is recommended for patients on and mantle cell and marginal zone lymphoma. The
dasatinib experiencing dyspnea to screen for pul- first-generation Bruton TKI ibrutinib notably in-
monary arterial hypertension. creases the risk for atrial fibrillation,64,65 primarily

The corrected QT interval should be reassessed in within 6 months of initiating treatment, 66 and in-
patients on chronic myeloid leukemia (CML) TKIs creases the risk for hypertension, which typically
who are prescribed other QT interval–prolonging emerges within the same time frame.67,68 Observa-
medications. tional studies suggest a potentially higher risk for HF
JACC: CARDIOONCOLOGY, VOL. 6, NO. 6, 2024 Leong et al 825
DECEMBER 2024:815–834 Managing Cardiotoxic Cancer Therapy

and ventricular arrhythmias with ibrutinib use. 26,27,69 metastatic non–small cell lung cancer, which ac-
Prompt control of hypertension is crucial for pre- counts for approximately 5% of cases of metastatic
venting adverse cardiovascular events associated non–small cell lung cancer. The most common cardiac
with ibrutinib. 67,70 complication associated with ALKI therapy is brady-
The reliance on ibrutinib has been somewhat cardia.76,77 The incidence of bradycardia with crizo-
reduced by alternatives that present a lower risk for tinib is significantly higher than with platinum-based
CTR-CVT; these alternatives include second- chemotherapy (19% vs 0.5%), 77 though most cases are
generation Bruton TKIs (acalabrutinib and zanu- mild. A meta-analysis of randomized ALKI trials re-
brutinib) and venetoclax. 71,72 Alternatives, either in ported a pooled incidence of bradycardia of 8%, with
the same class or from a different drug class, should a relative risk of 24.7 (95% CI: 7.1-85.7). 78 Notably,
be considered for patients with atrial fibrillation or HF next-generation ALKIs, such as alectinib and lorlati-
or those at high cardiovascular risk. nib, currently first-line therapies for anaplastic lym-
Studies show differences in atrial fibrillation rates phoma kinase–positive metastatic non–small cell lung
favoring acalabrutinib and zanubrutinib over ibruti- cancer, show similar bradycardia rates comparable
nib and less hypertension with acalabrutinib than with that of crizotinib. It is crucial to screen patients
ibrutinib. However, indirect evidence suggests that initiating ALKIs for bradycardia at baseline and to
atrial fibrillation and hypertension rates among those monitor them clinically during therapy.
treated with second-generation Bruton TKIs may still Hypertension has also been observed in patients
exceed those of untreated adults in this demographic. receiving brigatinib (23% vs 7% for crizotinib) and
Direct comparisons with placebo or nonibrutinib lorlatinib (18% vs 2% for crizotinib).79,80 More than
control subjects, providing high-level evidence, are one-half of these adverse effects are classified as
lacking. grade 3 or higher according to the Common Termi-
Bruton TKIs are known to increase bleeding risks. 73 nology Criteria for Adverse Events, necessitating
Most patients have CHA2DS 2-VASc scores >2,74,75 medical intervention. Therefore, it is essential to
indicating a potential need for anticoagulation if assess blood pressure at baseline and during subse-
atrial fibrillation develops. Bruton TKIs may interact quent clinic visits for patients receiving brigatinib or
with direct oral anticoagulant agents, verapamil, dil- lorlatinib. Additionally, in patients who develop hy-
tiazem, digoxin, and amiodarone. When using apix- pertension during therapy, the use of antihyperten-
aban or rivaroxaban concomitantly with a Bruton TKI, sive agents that could cause bradycardia should be
dose reductions should be considered. Alternatively, avoided when possible.
edoxaban, a direct oral anticoagulant agent less Hypercholesterolemia and hypertriglyceridemia
affected by CYP3A4 clearance, may be prescribed are common adverse effects in patients receiving
instead. lorlatinib.80 In the CROWN (A Study of Lorlatinib
ANAPLASTIC LYMPHOMA KINASE INHIBITORS. Versus Crizotinib in First Line Treatment of Patients
Recommendations. With ALK-Positive NSCLC) trial, these conditions

Patients starting anaplastic lymphoma kinase in- were reported in 70% and 64% of lorlatinib-treated
hibitors (ALKIs) should have their heart rate and patients, respectively, compared with 4% and 6% in
electrocardiogram recorded at baseline, with heart those treated with crizotinib. 80 Although the long-
rate rechecked at each clinic visit during follow-up. term risks associated with these lipid abnormalities

For patients receiving brigatinib or lorlatinib, blood are unknown, therapy with lipid-lowering agents is
pressure should be assessed at baseline and at each frequently required. It is recommended that lipid
subsequent clinic visit. profiles be assessed at baseline, then every 1 to

Patients receiving lorlatinib should have their 2 months until stabilized, followed by assessments
lipids checked at baseline, initially every 1 to every 3 to 6 months.
2 months until stable, and then every 3 to EPIDERMAL GROWTH FACTOR RECEPTOR
6 months. INHIBITORS.
Recommendations.
Gaps in knowledge.

It is recommended that patients receiving osi-

The optimal management strategy for patients
mertinib undergo baseline electrocardiography,
who develop severe bradycardia while on ALKIs
with subsequent electrocardiographic surveillance
remains undefined.
considered. Additionally, monitoring electrolytes
ALKIs are used primarily in the treatment and avoiding other QT interval–prolonging drugs
of anaplastic lymphoma kinase fusion–positive are recommended.
826 Leong et al JACC: CARDIOONCOLOGY, VOL. 6, NO. 6, 2024

Managing Cardiotoxic Cancer Therapy DECEMBER 2024:815–834

Baseline echocardiography is advised for those ICIs are associated with a broad range of cardio-
treated with osimertinib, with surveillance vascular toxicities. Although myocarditis is the most
considered for those at high risk. frequently described cardiovascular immune–related
adverse event, other conditions, such as pericardial
Gaps in knowledge.
diseases, vasculitis, arrhythmias, atherosclerotic and

The optimal dosing of osimertinib and manage-
thromboembolic events, and declines in LVEF
ment of corrected QT intervals in patients who
without evidence of myocarditis, have also been
exhibit QT interval prolongation are not known.
reported. The overall combined incidence of cardio-
Osimertinib, a third-generation epidermal growth vascular immune–related adverse events is approxi-
factor receptor inhibitor, is associated with a decline mately 3.1% with monotherapy and 6% with dual
in LVEF and QT interval prolongation. Post hoc therapy.85
analyses detected a 3.1% to 5.5% incidence of LVEF The cardiovascular immune–related adverse event
decline of $10% to an absolute value <50%.81 Risk most frequently described in the literature is
factors for LVEF decline include atrial fibrillation, myocarditis, with incidences ranging from 0.7% to
hypertension, diabetes, and hypothyroidism. Osi- 1.7%. Myocarditis typically manifests between 30 and
mertinib also shows 2 to 6 times higher odds of HF 50 days from the first ICI dose, with the majority
being reported to pharmacovigilance databases of cases detected within the first 3 months.85-89 ICI-
compared with other treatments. 82 associated myocarditis historically carries a poor
All patients receiving epidermal growth factor prognosis, with mortality rates ranging from 17% to
receptor inhibitors should have cardiovascular 30%, which is higher than non-ICI myocarditis, and is
risk factors assessed and undergo baseline often due to fatal arrhythmias and HF. 89 The primary
echocardiography, with echocardiographic surveil- risk factor for myocarditis is the use of combination
lance considered for those with risk factors for ICI therapy.89
cardiomyopathy. Baseline assessments of cardiac troponin and
Osimertinib is additionally associated with QT in- electrocardiography should be conducted to serve as
terval prolongation. 83,84 The risk in patients with comparators in the event of subsequent suspected
baseline heart rate–corrected QT interval prolonga- myocarditis. However, the utility of ongoing surveil-
tion is unknown because of trial exclusion criteria. All lance for ICI-associated myocarditis has not been
patients require baseline electrocardiography, and established. A prospective study monitoring cardiac
consideration should be given to ongoing electrocar- troponin during up to 10 doses of ICI treatment
diographic surveillance and electrolyte monitoring. showed that >10% of patients exhibited elevated
Concurrent QT interval–prolonging medications cardiac troponin levels, yet only 1.4% were ultimately
should generally be avoided. diagnosed with myocarditis. 86 Although biomarker
surveillance could potentially identify asymptomatic,
IMMUNE CHECKPOINT INHIBITORS.
smoldering myocarditis, it also carries the risk of
Recommendations.
unnecessary delays in ICI treatment.

Baseline assessments for immune checkpoint
Most patients with suspected myocarditis require
inhibitor (ICI) recipients should include mea-
inpatient evaluation. The gold standard for diagnosis
surement of cardiac troponin levels and electro-
involves an endomyocardial biopsy, which detects
cardiography.
infiltration of macrophages and T lymphocytes and

Hospitalization is recommended for most patients
evidence of myocyte necrosis. A risk for sampling
with suspected ICI myocarditis. For those diag-
error exists because of the patchy distribution of
nosed with ICI myocarditis or presenting with
these histopathologic findings. In the absence of
major cardiac events suspected to be myocarditis,
histopathologic data, diagnosis may rely on elevated
rapid initiation of high-dose corticosteroids is
cardiac troponin levels and cardiac magnetic reso-
recommended.
nance imaging. Although cardiac magnetic resonance
Gaps in knowledge. imaging has limited sensitivity, it offers high speci-

The role of using blood biomarkers, such as cardiac ficity and may show late gadolinium enhancement,
troponin, for ongoing surveillance of ICI myocar- T2 hyperintensity, or increase in native T1 or T2
ditis remains unclear. values. Additionally, echocardiography may reveal a

There is uncertainty regarding the optimal decline in LVEF or regional wall motion abnormalities
adjunctive therapies to high-dose corticosteroids or decreased global longitudinal strain, and abnormal
in the management of ICI myocarditis. electrocardiographic findings may be present.
JACC: CARDIOONCOLOGY, VOL. 6, NO. 6, 2024 Leong et al 827
DECEMBER 2024:815–834 Managing Cardiotoxic Cancer Therapy

Other important considerations include the pres- during anthracycline administration, it is crucial to
ence of other immune-related adverse events, rule out other causes of LV dysfunction and adopt a
particularly myositis and myasthenia-like syndromes, multidisciplinary approach to determine the safety of
as well as the timing of these events. Corticosteroids continuing or resuming anthracycline therapy. For
should be administered early once a diagnosis is patients with mild CTR-CVT, continuing anthracy-
confirmed, as observational data indicate that initia- cline treatment under close collaboration with a
tion within 24 hours of admission and higher initial cardio-oncology specialist may be reasonable.
corticosteroid doses are associated with a reduced However, for those with moderate or severe CTR-
risk for major adverse cardiac events. 90 Many patients CVT, permanent discontinuation of anthracyclines is
may be resistant to corticosteroids and require recommended. Exploring alternatives such as dexra-
second-line immunosuppressants, with options zoxane, liposomal doxorubicin, and other effective
including abatacept, mycophenolate, JAK-STAT in- cancer therapies with a lower risk for CTR-CVT should
hibitors, and intravenous immunoglobulin. However, also be considered.
the optimal approach remains undefined and war- If abnormal cardiac troponin levels, indicative of
rants further research. Effective management and subclinical myocardial injury, are identified during
diagnosis of ICI-associated cardiovascular toxicities anthracycline administration, the effectiveness of
require close collaboration between cardiologists and cardioprotective treatments remains uncertain. In
oncologists. a study involving 56 patients who experienced
increases in cardiac troponin levels shortly after high-
PERMISSIVE CTR-CVT dose cancer therapy (including anthracycline in some
instances), ACEIs were shown to prevent a decline in
Recommendations. LVEF compared with an open-label control group,

Permissive CTR-CVT should be individualized on and they also reduced the risk for developing overt
the basis of the patient’s type of cancer, the HF. 92 However, it is unclear if these results apply to
specific cancer therapy involved, and patient high-sensitivity cardiac troponin tests, which detect
preferences. smaller myocardial injuries.
Gaps in knowledge. Additionally, the rates of HF observed in the con-

The balance of relative risks and benefits associ- trol arm of this open-label study were substantially
ated with permissive CTR-CVT is still unclear for all higher at 24%, and LVEFs were markedly lower,
cancer therapies. compared with the expected HF rates of 6% and
typical LVEF in this population.13 In a more recent
The rationale of permissive cardiotoxicity in cancer trial using an open-label, blinded endpoint design,
therapies is that mild CTR-CVT may be considered candesartan and carvedilol vs control were tested in
acceptable if it is manageable and the therapeutic patients receiving $300 mg/m 2 doxorubicin who
benefits of the cancer treatment are clear. However, exhibited elevations in high-sensitivity cardiac
the nuances of different CTR-CVTs mean that strate- troponin I. This study revealed no difference in LVEF
gies for permissive cardiotoxicity must be tailored to between the groups, 93 Therefore, further research is
both the cancer therapy and the individual patient. needed to validate cardiac troponin as a marker for
ANTHRACYCLINES. subclinical CTR-CVT and to guide the use of ACEIs in
Recommendations. mitigating anthracycline-induced CTR-CVT.

The risks and benefits of continuing ongoing
anthracycline therapy in patients with LV HER2-TARGETED THERAPIES.
dysfunction should be evaluated in a multidisci- Recommendations.
plinary setting. Consideration should include the
It is feasible to continue HER2-targeted therapy in
use of dexrazoxane, liposomal doxorubicin, and individuals with mild, minimally symptomatic
alternate cancer treatments. LV dysfunction.

Gaps in knowledge. Gaps in knowledge.

The acute and long-term risk for HF in patients
The risks and benefits of permissive cardiotoxicity
with LV dysfunction treated with anthracycline, for HER2-targeted CTR-CVT are not fully under-
including liposomal doxorubicin, remains unclear. stood in large populations.

The management of anthracycline-induced CTR- Randomized control trials have demonstrated that
CVT aligns with that for LV systolic dysfunction of shorter courses of HER2-targeted therapy (<1 year) in
any etiology.91 In cases in which CTR-CVT develops early-stage breast cancer can lead to worse disease-
828 Leong et al JACC: CARDIOONCOLOGY, VOL. 6, NO. 6, 2024

Managing Cardiotoxic Cancer Therapy DECEMBER 2024:815–834

free and overall survival. 94 Observational data sug- mechanism behind this chest pain in the setting of 5-
gest that any interruptions in HER2-targeted therapy FU is thought to be coronary vasospasm. Typically,
may be associated with poorer outcomes.95 These vasospasm occurs within the first few cycles of 5-FU
findings prompted 2 prospective single-arm trials to treatment, with nearly 90% of cases presenting dur-
evaluate the management of reduced LVEF in pa- ing their initial 3 doses (>70% during the first cycle).101
96,97
tients receiving HER2-targeted therapies. In both More than 95% of these cases present with chest pain,
studies, all participants were closely observed with and >70% show ST/T-wave changes on admission
serial echocardiography, and ACEIs and beta-blockers electrocardiography.101 Other less common effects
were administered at the highest tolerated doses. include arrhythmias, pericarditis, myocarditis, HF,
HER2-targeted therapy was discontinued only if the and even death.99 The reported incidence of these
LVEF dropped to <35% to 40% or if moderate HF complications varies very widely in the literature,
symptoms developed. Although the approach was from 1% to >30%, 100 depending on the population
deemed feasible, a 5% to 10% incidence of moderate studied, outcome definitions, and the drug’s formu-
to severe HF or LV impairment necessitating the lations or administration protocols.
discontinuation of HER2 therapy was observed with There is currently no clear consensus on the inci-
permissive CTR-CVT.98 The risk-benefit relationship dence, risk factors, and prognosis of 5-FU-associated
of this approach has not been fully evaluated, and the coronary vasospasm.101,102 Patients exhibiting sus-
net clinical benefit regarding cancer-free survival re- pected 5-FU-associated vasospasm should be referred
mains uncertain. Up to 14% of patients treated with to an emergency department, where 5-FU adminis-
permissive CTR-CVT exhibited evidence of LV tration is paused, and nitrates are administered
impairment at 18-month follow-up, though this rate acutely. Discontinuing 5-FU administration typically
may be confounded by prior anthracycline exposure resolves the chest pain. Many health care centers also
and could plausibly be lower in those not treated with recommend work-up for obstructive coronary dis-
anthracyclines. 98 Further research is needed to define ease; in the acute cases, many patients undergo cor-
the role of permissive CTR-CVT with HER2-targeted onary angiography because of electrocardiographic
therapy. changes and the presence of chest pain.103
FLUOROPYRIMIDINES. There are no definitive data on the optimal man-
Recommendations. agement of patients experiencing 5-FU vasospasm.

Chest pain syndromes suspected to be caused by However, some studies suggest benefits from pro-
5-fluorouracil (5-FU)–induced or capecitabine- phylactic use of nitrates 103,104 or calcium-channel
induced coronary vasospasm should be acutely blockers104 or switching from infusional to bolus-
treated with nitrates and/or calcium-channel only 5-FU 105 to reduce the likelihood of recurrent
blockers. vasospasm. When considering a rechallenge, it is

After suspected coronary vasospasm, nitrates often advised to use a combination of the aforemen-
and/or calcium-channel blockers should be con- tioned cardioprotective medications. If a permissive
sidered. If rechallenging with 5-FU or capecitabine CTR-CVT approach is desired, rechallenging the pa-
is planned, it should be conducted in a closely tient in an inpatient setting should be considered, 104
monitored setting. especially when there is clear evidence of myocar-
dial ischemia or infarction. Alternatively, for patients
Gaps in knowledge. who exhibit early-onset, severe, or life-threatening

The risks and benefits of fluoropyrimidine toxicity occurring within 96 hours after the adminis-
permissive CTR-CVT are unknown. tration of 5-FU or capecitabine, uridine triacetate is
5-FU is used in treating adenocarcinomas of the approved by the U.S. Food and Drug Administration
breast, as well as adenocarcinomas and squamous cell for emergency use. 106
carcinomas of the bladder, gastrointestinal tract, and OTHER THERAPIES. Rechallenging patients with
head and neck. Annually, more than 150,000 patients other cancer therapies, such as various TKIs, VEGFIs,
in the United States are treated with 5-FU or capeci- and ICIs after the development of CTR-CVT may be
tabine, making 5-FU the third most common drug considered. However, the support for the efficacy and
used for solid malignancies.99 safety of permissive cardiotoxicity with these agents
The most common manifestation of 5-FU-associ- is currently limited, with evidence drawn only from
ated CTR-CVT is chest pain, 100 which can vary from case reports and small case series. Consequently,
atypical chest pain to typical angina, acute coronary there are insufficient data to form evidence-informed
syndrome, and myocardial infarction.100 The principal recommendations. Clinical decision making should
JACC: CARDIOONCOLOGY, VOL. 6, NO. 6, 2024 Leong et al 829
DECEMBER 2024:815–834 Managing Cardiotoxic Cancer Therapy

be individualized on a case-by-case basis, taking into myeloproliferative neoplasms. Additionally, anti-

account the patient’s goals of care and involving platelet activity from therapies such as Bruton TKIs
cancer specialists and cardiologists in the process. may also contribute to bleeding. This propensity for
bleeding can lead to significant pharmacodynamic
MANAGEMENT OF SEVERE DDIs when patients are concurrently treated with
CARDIOVASCULAR DISEASE antithrombotic medications for conditions such as
coronary artery disease and atrial fibrillation.
Recommendations. QT interval prolongation, which increases the

It is recommended that the decision to use invasive risk for torsades de pointes, is often seen with phar-
cardiovascular interventions in patients with macodynamic interactions between QT interval–
advanced malignancies be guided by a multidisci- prolonging medications, used in both treatment
plinary team. (eg, ribociclib, doxorubicin, sunitinib) and supportive
(eg, ondansetron, citalopram, methadone) contexts.
Gaps in knowledge.
Additionally, in cancer treatment settings, symptoms

The net clinical benefit of invasive cardiovascular
such as vomiting, diarrhea, and poor oral intake can
interventions in patients with advanced malig-
exacerbate this risk through electrolyte abnormal-
nancies is unknown.
ities. It is crucial to recognize these cancer-related
There are limited data from randomized controlled factors when prescribing cardiovascular medications
trials or comprehensive prospective cohort studies to that also prolong the QT interval, such as sotalol,
inform the role of invasive cardiovascular in- amiodarone, and class I antiarrhythmic drugs. The
terventions in patients with severe cardiovascular benefits and risks of using concomitant QT interval–
disease who also have metastatic cancer with a prolonging drugs should be considered, with close
guarded cancer-specific prognosis. 107 Therefore, de- monitoring of the corrected QT interval.
cision making for these patients should be highly Pharmacokinetic interactions are frequently asso-
individualized and inclusive of all relevant stake- ciated with drug metabolism, particularly involving
holders. Key factors to consider in this decision- CYP enzymes. The CYP enzymes most commonly
making process should include 1) the expected implicated include CYP1A2, CYP2C8, CYP2C9,
magnitude and immediacy of benefits from the CYP2C19, CYP2D6, and CYP3A4 (Table 4). A drug may
invasive cardiovascular procedure; 2) potential risks inhibit and be metabolized by the same enzyme, or it
associated with the procedure; 3) the prognosis of the can act as both an inhibitor and an inducer for
malignancy; 4) the patient goals of care and comor- different enzymes. When 2 drugs competitively
bidities (including thrombocytopenia); and 5) the inhibit each other or inhibit the same enzyme, the
consequences of interruptions during cancer effects can be competitive or synergistic. Addition-
treatments. ally, a medication that is a substrate for multiple
CYP enzymes may exhibit variable clinical signifi-
SPECIFIC CONSIDERATIONS cance in its interactions. Other pathways such as
P-glycoprotein and UGT also play important roles in
DDIs. the clearance of medications and are significant
Recommendations. in pharmacokinetic DDIs.

It is recommended to consider the possibility of Empirical data to inform the effects of cardio-
DDIs whenever prescribing new cancer or cardio- oncologic DDIs are limited. Generally, DDIs are
vascular medications. predicted on the basis of analogous observations of
interactions between other drugs metabolized by the
Gaps in knowledge.
same CYP enzymes. The decision to avoid or accept

Direct knowledge about the consequences of
anticipated DDIs should be tailored on the basis of the
coprescribing drugs with potential DDIs is limited.
clinical importance of the respective drugs involved.
The pharmacodynamic DDIs most relevant to A comprehensive review of drug interactions has
cardio-oncology include QT interval prolongation been published.108 Specific cardiovascular DDIs that
and bleeding. Bleeding risks can arise from cancer are frequently encountered include interactions with
therapies that induce thrombocytopenia, such as diltiazem, verapamil, and amiodarone, which inhibit
myelosuppressive chemotherapy regimens, stem several CYP enzymes. Among oral anticoagulant
cell transplantation, and JAK2 inhibitors such as agents, apixaban is a substrate of CYP3A4 and
ruxolitinib and fedratinib used in treating CYP3A5; dabigatran etexilate and edoxaban are
830 Leong et al JACC: CARDIOONCOLOGY, VOL. 6, NO. 6, 2024

Managing Cardiotoxic Cancer Therapy DECEMBER 2024:815–834

T A B L E 4 Potential Cardio-Oncology Drug-Drug Interactions Related to Moderate or Strong CYP or P-gp Interactions

Substrate Inhibitor Inducer

Drug Type Drug 2C9 2C8 2C19 2D6 3A4 P-gp 2C9 2C8 2C19 2D6 3A4 P-gp 2C9 2C19 2D6 3A4 P-gp

Antithrombotic Warfarin X
Apixaban X Xa
Rivaroxaban X Xa
Edoxaban X
Dabigatran X
Clopidogrel X X
Ticagrelor X
Lipid lowering Atorvastatin X
Gemfibrozil X
Antiarrhythmic/atrial fibrillation Flecainide X
Dronedarone X X X
Amiodarone X X
Verapamil X X X
Diltiazem X X
Pulmonary hypertension Sildenafil X
CLL/SLL/mantle cell lymphoma Ibrutinib X
Acalabrutinib X
GI/liver cancer Regorafenib X
Lung cancer Osimertinib X
Prostate cancer Abiraterone X X
Enzalutamide X X X X X X
Apalutamide X X X X
Breast cancer Tamoxifen X X
Exemestane X
Ribociclib X X
Tucatinib X X X X
AML Midostaurin X
Ivosidenib X
CML Imatinib X X
MM, AL amyloidosis Bortezomib X
Melanoma Dabrafenib X X X
Breast, GU Olaparib X
Cytotoxic chemotherapy Doxorubicin X X X
Paclitaxel X X

Only moderate or strong CYP inducers or inhibitors are included. aMinor P-gp substrates may generally pose less risk, but if a drug acts as both a CYP3A4 and a P-gp inhibitor or inducer, it may result in a more
clinically significant interaction. Sources: UpToDate, Lexicomp, product monograph pharmacokinetic information, and Beavers et al.108
AL ¼ amyloid light chain; AML ¼ acute myeloid leukemia; CLL ¼ chronic lymphocytic leukemia; CML ¼ chronic myeloid leukemia; CYP ¼ cytochrome P450; GI ¼ gastrointestinal; GU ¼ genitourinary;
MM ¼ multiple myeloma; P-gp ¼ P-glycoprotein; SLL ¼ small lymphocytic lymphoma.

substrates of P-glycoprotein; and rivaroxaban is a Gaps in knowledge.

substrate of CYP3A4, CYP3A5, and P-glycoprotein.
The optimal surveillance strategy for CTR-CVT
Once a DDI is identified, management strategies after immunotherapy is not known.
may include close monitoring, dose modification,
Chimeric antigen receptor T cell therapy modifies T
transitioning to an alternative therapy, or discontin-
lymphocytes to target specific antigens, thereby
uation. Involving a multidisciplinary team, including
redirecting immune effector cells against those anti-
a clinical oncology or cardiology pharmacist, can be
gens, such as CD19 in lymphomas and BCMA in mul-
instrumental in identifying and addressing DDIs in
tiple myeloma.
the cardio-oncology patient population.
Although chimeric antigen receptor T cell thera-
NEWER IMMUNOTHERAPIES. pies have drastically improved outcomes for hema-
Recommendations. tologic cancers, they are associated with unique

It is recommended to consider baseline cardiac toxicities, such as cytokine release syndrome (CRS).
troponin, electrocardiography, and echocardiogra- CRS is an acute inflammatory reaction that can range
phy before initiating immunotherapy. from mild symptoms such as isolated fever (grade 1)
JACC: CARDIOONCOLOGY, VOL. 6, NO. 6, 2024 Leong et al 831
DECEMBER 2024:815–834 Managing Cardiotoxic Cancer Therapy

to severe complications such as multiorgan failure with underlying or recent cardiac toxicity, effective
(grade 4). 109-111 Cardiovascular toxicities are most management of these patients should include the
frequently observed during CRS episodes. The un- identification of any cardiac comorbidities and the
derlying mechanism is not entirely understood but is prompt management of CRS to prevent any cardio-
thought to be related to an acute inflammatory vascular decompensation.
response, particularly affecting individuals with pre- SUMMARY. The European Society of Cardiology has
existing cardiovascular conditions or risk factors. published detailed cardio-oncology clinical guide-
The reported overall incidence of cardiovascular lines.6 The present expert panel report focuses on
toxicities varies, with rates ranging between 12% and providing practical recommendations during cancer
21%, including HF (4%-13%), myocardial infarction therapy supported by high-quality evidence that can
(5%), cardiogenic shock (2%), and arrhythmias be applied across diverse settings while also high-
(4%).112-115 In clinical trials with carefully selected lighting the significant knowledge gaps in the field of
patients, a lower incidence of cardiovascular toxic- cardio-oncology. The identification, prevention, and
ities is reported, such as a 0.5% to 1% incidence of management of CTR-CVT should be driven by
reduced LVEF and a 0.5% incidence of cardiac ar- outcomes-based data. In areas in which such data are
rest.116,117 Retrospective studies report higher rates, lacking, management should be tailored to the indi-
with wide variations depending on the definition vidual needs of each patient.
used, cohort studied, and type of study.
ACKNOWLEDGMENT The authors are grateful for
The optimal strategy for surveillance strategy for
Michelle Lui’s comments on the manuscript.
cardiovascular toxicities after Chimeric antigen re-
ceptor T cell therapy is unknown, including the roles
FUNDING SUPPORT AND AUTHOR DISCLOSURES
of biomarkers and serial echocardiography. In the
absence of robust data, we recommend a baseline
Dr Leong has received consulting fees or honoraria from AbbVie,
assessment of comorbidities and consideration of Ferring, Ipsen, Jazz, Myovant Sciences, Novartis, Pfizer, Sanofi, Tol-
initial tests such as baseline cardiac troponin, N-ter- mar, Antev, AstraZeneca, and Boston Scientific; and has received

minal pro–B-type natriuretic peptide, electrocardiog- research grants from Novartis and Tolmar. Dr Waliany has received
consulting fees from AstraZeneca. Dr Abdel-Qadir has received
raphy, and echocardiography for patients being
speaker honoraria from Jazz Pharmaceuticals and AstraZeneca. Dr
evaluated for this therapy. Special attention and Atkins has received honoraria from OncLive. Dr Neilan has received
proactive optimization of treatment should be consulting fees from Bristol Myers Squibb, RACE Oncology, Roche,
Genentech, Roivant, and Sanofi; and has received grant fees from
directed at patients with pre-existing cardiovascular
Bristol Myers Squibb, AstraZeneca, and Abbott. Dr Lang has received
conditions, particularly those related to previous
research grants from Roche Diagnostics, Astra Zeneca, and Boehringer
treatments such as anthracyclines. Prompt treatment Ingelheim; and has received consulting fees and honoraria from
of CRS with agents such as tocilizumab is crucial to Roche Diagnostics, Myokardia, Pharmacosmos, Akero Therapeutics,
CV6 Therapeutics, Jazz Pharmaceuticals, and Novartis. Dr Moore has
mitigate the effects of CRS and potentially prevent
received consulting fees from AstraZeneca, Daiichi-Sankyo, Eli Lilly,
the onset of subsequent cardiovascular toxicities. As Novartis, RACE Oncology, and Pfizer. Dr Mian has received research
these therapies become more prevalent in oncology, support from Janssen; and has received honoraria and consulting fees
ongoing collaboration between cardiologists and on- from Janssen, Pfizer, Sanofi, Bristol Myers Squibb, Takeda, Amgen,
and FORUS. Dr Morgans has received consulting fees from Astellas,
cologists is essential to optimize patient outcomes
AstraZeneca, AAA, Bayer, Janssen, Exelixis, Lantheus, Myovant Sci-
and minimize the risk for cardiovascular toxicity in ences, Merck, Pfizer, Novartis, Sanofi, and Telix. Dr Ellis has received
real-world settings. honoraria from AstraZeneca, Bristol Myers Squibb, Eli Lilly, Janssen,
Bispecific antibodies are an emerging class of Jazz Pharmaceuticals, Merck, Novartis, Roche, Sanofi, and Pfizer. Dr
Dent has received honoraria from Pfizer, AstraZeneca, Gilead Sci-
immunotherapeutic agents used in hematologic ma-
ences, Novartis, Bristol Myers Squibb, and Myocardial Solutions. All
lignancies such as leukemia, multiple myeloma, and other authors have reported that they have no relationships relevant
lymphoma. These antibodies function by binding to 2 to the contents of this paper to disclose.

targets: one on tumor cells and one on T cells, which

activates the T cells and leads to the destruction of ADDRESS FOR CORRESPONDENCE: Dr Darryl Leong,
cancer cells. Bispecific antibodies can cause grade 3 Hamilton General Hospital, 237 Barton Street East,
CRS in 1% to 7% of patients, characterized by fever, C2-238 David Braley Building, Hamilton, Ontario L8L
hypotension requiring vasopressors, and/or hypox- 2X2, Canada. E-mail: [email protected]. X handle:
ia.118 Because clinical trials often excluded patients @DarrylLeong.
832 Leong et al JACC: CARDIOONCOLOGY, VOL. 6, NO. 6, 2024

Managing Cardiotoxic Cancer Therapy DECEMBER 2024:815–834

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