Accepted Manuscript: Management and Treatment of Cardiotoxicity Due To Anticancer Drugs: 10 Questions and Answers

1 Management and treatment of cardiotoxicity due to anticancer drugs: 10 questions and answers
4 Michela Chianca,a Iacopo Fabiani, MD, PhD,b Annamaria Del Franco, MD,a,b Chrysanthos Grigoratos,
5 MD, PhD,b Alberto Aimo, MD,a,b Giorgia Panichella,a Alberto Giannoni, MD, PhD,a,b Vincenzo
Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac170/6658185 by guest on 09 August 2022

PT
6 Castiglione, MD,c Francesco Gentile, MD,c Claudio Passino, MD, PhD,a,b Carlo Maria Cipolla,MD,d
7 Daniela Maria Cardinale, MD, PhD,d Michele Emdin, MD, PhD,a,b
RI
8
9 a. Institute of Life Sciences, Scuola Superiore Sant’Anna, Pisa, Italy
SC
10 b. Cardiology Division, Fondazione Toscana Gabriele Monasterio, Pisa, Italy
11 c. Cardiology Division, Pisa University Hospital, Pisa, Italy
12 d. Cardioncology Unit, Cardiology Division, European Institute of Oncology, I.R.C.C.S. Milan, Italy.
U
13
14 Short title: 10 questions in cardioncology N

A
15 Conflicts of interest: none
16
M
17 Address for correspondence:

18 Iacopo Fabiani, MD, PhD
19 U.O.Cardiologia e Medicina Cardiovascolare
D
20 Fondazione Toscana Gabriele Monasterio

21 Viale G. Moruzzi, 1 – 56100, Pisa, Italy
TE
22 E-Mail address: iacopofabiani@gmail.com -Phone: 050-3152216- Fax: 050-3153229

23
EP
24
25
CC
26
27
A
28
29
30
© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights
reserved. For permissions, please e-mail: journals.permissions@oup.com This article is published and distributed under
the terms of the Oxford University Press, Standard Journals Publication Model
(https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) 1
1
2 Abstract
4 Since the introduction of anthracyclines into clinical practice in the 1960s, chemotherapy have always

PT
5 been associated to cardiotoxicity. Patients on cardiotoxic drugs can develop a wide range of
6 cardiovascular diseases, including left ventricular (LV) systolic dysfunction and heart failure (HF),
RI
7 arrhythmias, hypertension, and coronary artery disease (CAD). The rising number of cancer patients,
8 population aging, and the frequent overlap of cardiovascular and oncological diseases have highlighted
SC
9 the importance of close collaboration between cardiologists and oncologists. As a result, in 1995,
10 cardiologists at the IEO (European Institute of Oncology) coined the term cardioncology, a new
U
11 discipline focused on the dynamics of cardiovascular disease in cancer patients. Given the complex
12 scenario characterized by a constant dialogue between the oncological condition and cardiovascular
13 N
comorbidity, it is essential for the clinician to get the knowledge to properly fulfill the needs of the
A
14 oncological patient under cardiotoxic treatment.
M
15 Through the answer to 10 questions, we aim to describe the complex issue of cardiotoxicity by
16 addressing the main critical points and current evidence related to the assessment, management,
D
17 treatment and surveillance of cancer patients under chemotherapy.

TE
18 Keywords: cardiotoxic; cardiac biomarker; ventricular function; chemotherapy; cardio protection;

19 Heart failure
20
EP
21
22
CC
A
2
1 INTRODUCTION
2
3 The development of cardiotoxicity from antitumor drugs was first recognized in the early ‘60s, with the
4 introduction of anthracyclines into clinical practice. Over the following decades, earlier diagnosis and
5 advances in cancer therapy have led to a significant improvement of outcomes. The increasing number

PT
6 of cancer survivors, together with the use of combination treatments with synergistic cardiotoxic
7 effects, makes cardiotoxicity a relevant limitation of many anticancer agents.
RI
8 The manifestations of cancer drug cardiotoxicity are broad, including left ventricular (LV) systolic
9 dysfunction and heart failure (HF), arrhythmias, hypertension and coronary artery disease (CAD).
SC
10 Nonetheless, the current definition focus on cancer therapy-related cardiac dysfunction (CTRCD) (1).
11 Patients who are candidates to cardiotoxic therapies should be followed closely to detect a cardiotoxic
U
12 damage before it becomes clinically evident. Echocardiography is a useful tool to assess parameters
13 such as LV ejection fraction (LVEF) and global longitudinal strain (GLS), the latter to detect
14 N
subclinical cardiac damage. Cardiac biomarkers, natriuretic peptides and high-sensitivity troponins are
A
15 gaining interest as they offer the possibility to detect cardiotoxic damage in an early phase and possibly
M
16 to predict future development of CTRCD (2,3).
17 In the present review we will dissect the major principles of cardiotoxicity by answering ten questions
18 (Figure 1), with the goal of providing a valuable tool for clinicians in managing patients who are at risk
D
19 of developing cardiotoxicity. Given the many open issues in the field of cardionocology and the
TE
20 growing interest in this branch, we will try to bring the growing problem of cardiotoxicity from
21 chemotherapy to the attention of non-specialist physicians so that they can provide proper treatment
EP
22 and prevention to their patients.

23
CC
24 1. How is cardiotoxicity defined and classified?

25
26 The American Society of Echocardiography (ASE) and the European Association of Cardiovascular
A
27 Imaging (EACVI) have defined cardiotoxicity (or CTRCD) as LVEF decrease ≥10% to a value of
28 <53%, as assessed by either two- or three-dimensional echocardiography, cardiac magnetic resonance
29 (CMR) or multi-gated acquisition scan (1).
30 Hypertension, vascular toxicity, cardiac dysfunction, myocarditis, and arrhythmias are
31 the five basic signs of cardiotoxicity mentioned in the Intentional Cardio -Oncology
32 Society (IC-OS) consensus statement (4). Hypertension is identified as any increase in
3
1 systolic and/or diastolic blood pressure following the start of cancer treatment, without
2 any other contributory alterations, above the diagnostic threshold of 130/80 mmHg.
3 Vascular toxicity, which comprises a variety of diseases (including stroke, pheripheral
4 ischaemia, thromboembolic event ect.), is characterised by the induction or exacerbation
5 of vascular pathology produced by chemotherapy. According to accepted criteria,

PT
6 vascular toxicity may be temporary or persistent, symptomatic or asymptomatic.
7 Regarding the direct damage to the heart, cardiotoxicity is defined as any structural or
RI
8 functional cardiac abnormality brought on by the administration of anticancer therapy,
9 whether asymptomatic or characterized by mild to severe symptomatology and clinical
SC
10 heart failure (HF). Major and minor diagnostic criteria are used to define myocarditis,
11 which can present as direct damage or immune -mediated inflammation of the
U
12 myocardium in association with a variety of anti -cancer therapy. Finally,
13 supraventricular and ventricular arrhythmias, determined by established standard
14 N
practice, and/or QT prolongation may occur; according to the Fridericia formula, a
A
15 prolonged QT interval >500 ms is defi ned as prolonged.
M
16 There are several classifications of cardiotoxicity, according to time of onset, clinical,
17 echocardiographic or biohumoral criteria. One of the first classifications of cardiotoxic drugs
D
18 categorized them into type I drugs, causing irreversible cardiac damage (such as anthracyclines), and
19 type II drugs, causing reversible cardiac damage (such as trastuzumab). (1) However, several studies
TE
20 conducted since 2011 have questioned this classification, demonstrating both the partial reversibility
21 of type 1 drug toxicity and the occurrence of some irreversible damage from type 2 drug use. (2)
EP
22 Cardiotoxicity can also be classified as acute or chronic, the latter being classifiable as early-onset or
23 late-onset (Table 1). Using data from the Royal Brompton Hospital, a more recent classification of
CC
24 cardiotoxicity divides patients into six classes based on echocardiographic and biohumoral values as
25 well as the presence or absence of symptoms (5) . In addition, the International Cardio-Oncology
26 Society (IC-OS) has recently introduced a revised classification (Table 1)(4).
A
27
28 2. How is risk stratification performed?
29
30 It is common practice to assess the cardiovascular risk profile before starting cancer treatment. This can
31 improve cancer outcomes by reducing interruptions in cancer treatment due to cardiovascular events,
32 thus allowing a safer use of potentially cardiotoxic medications. Risk factors can be categorized as
4
1 patient-related (demographic and age-related [<18 years and >65 years], life-style risk factors,
2 cardiovascular history or risk factors; female gender; history) or treatment-related (regimens, doses,
3 concurrent therapies). Treatment-related factors include high-dose chemotherapy, previous use of
4 anthracycline, mediastinal radiation, and use of specific agents related to cardiotoxicity. All
5 anthracycline doses are associated with a risk for developing HF, and cardiotoxicity may occur even at

PT
6 low doses.
7
RI
8 Ghideon et al. developed a 7-factor risk score stratifying patients based on their risk of developing HF
9 or cardiomyopathy over a 3-year period; the risk for cardiotoxicity can be classified as low (<20%),
SC
10 medium (21–39%), or high (>40%) (3). Patients at low risk should continue to receive the potentially
11 cardiotoxic treatment under cardiovascular surveillance, according to international guidelines. Patients
U
12 with a medium risk should have their cardiovascular health closely monitored during treatment or be
13 referred to a Cardio-oncology or Cardiology evaluation. Patients with a high risk are referred to a
14 N
Cardio-oncology or Cardiology evaluation, possibly in a Cardio-oncology specialist service, to
A
15 optimize the management of their cardiovascular disease and modifiable risk factors. Of note, whether
M
16 the use of such score could help to identify the patients which could benefit more from preventive
17 therapies remains a key question to be addressed by future dedicated studies.
18 Herrmann et al. have proposed the Cardiotoxicity Risk Score, a model that assesses both patient-
D
19 and treatment-related risk factors. Scale values range from 0 to 4, in an increasing order of risk (6).
TE
20 Currently, there are not sufficient data to include these risk scales into routine clinical practice; none of
21 these risk scores has been prospectively validated and there is a need for future studies to clarify their
EP
22 reliability. It would also be useful to promote the introduction of electronic tools or apps for risk
23 stratification to be used in clinical practice. Finally, proteomic methods could allow a better profiling of
CC
24 patients who may be at low risk but have shown susceptibility to complications during follow-up.
25
26 3. Does HF predispose to the development of cancer?
A
27
28 Several studies have shown that patients with HF are at higher risk of developing cancer (7,8). HF and
29 cancer share common risk factors, such as aging, male sex, obesity, diabetes mellitus, sedentariness,
30 and smoking (9). They might both be induced by a common systemic disturbance, and HF might
31 promote cancer development (7). Inflammation and oxidative stress are two of the main pathways
32 involved in the etiopathogenesis of cancer and HF, promoting a tumorigenic microenvironment and
5
1 cancer invasiveness. Moreover, increased activation of the sympathetic nervous system and the renin–
2 angiotensin–aldosterone system (RAAS) have been also shown to promote several steps in cancer
3 development (7). Some cardiac stress biomarkers, such as N-terminal pro-B-type natriuretic peptide
4 (NT-proBNP), have been shown to be related to cancer disease progression and severity (8).
5 Additionally, HF is associated with enhanced tumor growth; this could be caused by cardiac excreted

PT
6 factors, such as SerpinA3, which could stimulate tumor growth via the Akt pathway (7). In turn, cancer
7 development may impair the precarious homeostasis of HF patients, increase their risk of developing
RI
8 CRTCD, and worsen their prognosis (9).
9
SC
10 4. Is cancer itself a condition predisposing to HF?
11
U
12 Cancer itself might represent a condition at increased risk of developing HF (10). Cancer-related
13 inflammation and oxidative stress might support the development of cardiac damage by sustaining
14 N
microvascular endothelial dysfunction. (11). Furthermore, increased RAAS activity and autonomic
A
15 dysfunction due to cancer might foster HF progression (12). Preclinical studies have also shown that
M
16 several oncometabolites (e.g., D-2-hydroxyglutarate) may promote cardiac dysfunction (13). An active
17 cancer has been associated with raised levels of cardiac biomarkers in treatment-naïve cancer patients,
18 and this increase predicts adverse outcomes (8). Untreated cancer patients often display an initial
D
19 impairment of ventricular structure and function (14), autonomic dysfunction (12) and reduced exercise
TE
20 capacity with a marked reduction in peak oxygen consumption (15).

21 Despite the growing interest in the subclinical cardiac damage in cancer patients before
EP
22 antineoplastic treatments,
23 further studies are needed to assess the subclinical cardiac damage in cancer patients naïve to
CC
24 chemotherapy, possibly using cardiac biomarkers or CMR.

25
26 5. Diagnosis and monitoring of cardiotoxicity
A
27 5a. Which are the imaging techniques used to study cardiotoxicity?

28
29 Echocardiography and CMR are the most widely used, with some limited use of nuclear imaging,
30 namely positron emission tomography, when CMR is not an option.
31 LVEF reduction is not a sensitive measure of cardiotoxicity, and changes in myocardial deformation
32 occur before a decline in LVEF or symptomatic HF; a treatment strategy based on changes in LVEF,
6
1 risks of delaying a timely diagnosis and subsequent treatment. GLS has been proposed as a potentially
2 strong and sensitive diagnostic and prognostic marker of subclinical ventricular dysfunction (1). A drop
3 in the absolute value of strain ranging from 10% and 15% indicates cardiotoxic injury. An
4 echocardiographic screening was conducted comparing GLS-based approach with a standard LVEF-
5 based approach in high-risk patients. However, no difference was seen in LVEF or GLS at 1 year (16).

PT
6 Although impaired LV systolic function holds diagnostic and prognostic significance, an ideal
7 echocardiographic parameter has not been found yet.
RI
8 The introduction of CMR into routine clinical practice may be helpful in patients with poor acoustic
9 window or when echocardiographic and clinical findings are discordant. As an alternative to ultrasound
SC
10 data, comprehensive tissue characterization provided by CMR could assist in identifying early forms of
11 cardiotoxicity before major structural damage. The evidence has been conflicting up to this point, and
U
12 their routine clinical use is still constrained by their restricted availability and high cost.
13
14 5b. Is there a defined biomarker-based approach? N
A
15
M
16 Biomarkers offere a promising complementary tool to imaging techniques for cardiotoxicity
17 surveillance (17-19)(Table 2).
18 The most studied biomarkers of cardiac injury in cardio-oncology are cardiac troponins (cTn) and
D
19 natriuretic peptides (NPs). After anthracycline-based chemotherapy, cTn elevation often precedes
TE
20 changes in LVEF (18), and troponin I is a predictive marker of occurrence and severity of
21 cardiotoxicity, both in patients treated with anthracyclines (3) and those on combination regimens,
EP
22 including trastuzumab (2). Moreover, troponin I has a 99% negative predictive value for cardiotoxicity
23 (3). High-sensitivity (hs) cTn assays have the potential for an even earlier detection of acute
CC
24 cardiotoxicity (19).
25 BNP and NT-proBNP are markers of increased LV wall stress routinely used for the diagnosis and
26 management of HF. Their measurement allows to assess the risk of cardiotoxicity and help determine
A
27 the degree of cardiac dysfunction (17). However, there is a significant heterogeneity across studies in
28 terms of biomarker assays, cut-off values and timing of measurement (18);. Moreover, NP levels
29 should be interpreted based on advanced age, female sex, kidney disease and cancer itself (20).
30 Markers of cardiac remodeling such as soluble suppression of tumorigenesis-2, galectin-3 and
31 growth differentiation factor-15, have not demonstrated to be effective in predicting cardiotoxicity (17,
32 19) as well as biomarkers of inflammation (17) (Table 2). In contrast, myeloperoxidase, a marker of
7
1 oxidative stress (11), has shown additive value compared to hsTnI for predicting cardiotoxicity in
2 patients receiving doxorubicin and trastuzumab (19).
3 Several studies have shown promising results for microRNA (miRNA) use in cancer patients treated
4 with anthracyclines (18). In particular, miR-1 has shown to predict doxorubicin-induced cardiotoxicity
5 in breast cancer patients with greater accuracy than cTnI (18).

PT
6 Large prospective studies with long-term follow-up are needed to standardize both the timing of
7 sampling and the assay methods to detect specific biomarkers for different cancer therapies (19).
RI
8
9 5c. How should imaging techniques and biomarkers be combined?
SC
10 Imaging parameters and biomarkers of cardiac damage have intrinsic limitations when used alone for
11 cardiotoxicity surveillance. Indeed, structural changes are not suitable for early detection of
U
12 cardiotoxicity, whereas biomarkers such as hs-cTn are not specific for CTRCD. A hybrid strategy
13 combining circulating biomarkers and non-invasive cardiac imaging may overcome the limitations of
14 N
the use of a single approach, potentially allowing an even earlier detection of cardiotoxicity.
A
15 A study on 81 women with breast cancer treated with cardiotoxic chemotherapy showed that a
M
16 combination of >19% decrease in peak longitudinal strain and >30 ng/L increase in hsTnI after a 3-
17 month therapy had a 93% specificity (vs. 73% for each parameter alone) for prediction of
18 cardiotoxicity (21). Based on these preliminary results, the EACVI has suggested an integrated
D
19 approach including the assessment of LVEF, GLS and cTn levels at baseline and during follow-up (1).
TE
20 Despite some promising results, there is no solid evidence about a multimodal approach to
21 cardiotoxicity surveillance. In particular, it is unknown which combination of imaging parameters and
EP
22 biomarkers holds the best positive and negative predictive values to detect cardiotoxicity, the optimal
23 timing for evaluation, and the possibility to predict late cardiotoxicity.
CC
24
25 6. Which are the optimal strategies for primary and secondary prevention?
26
A
27 According to the 2016 ESC Position Paper on Cancer Treatments and Cardiovascular Toxicity, the
28 only primary prevention strategies valid for all types of chemotherapy are treatment of comorbidities
29 and cardiovascular risk factors. To mitigate anthracycline toxicity, dose reduction, use of liposomal
30 formulations or continuous infusion are recommended. (22-23) (Table 3). To date, dexrazoxane is the
31 only drug specifically approved for the primary prevention of anthracycline-related cardiotoxicity (22).
32 Its use is currently approved for adults with advanced metastatic breast cancer who have received a
8
1 cumulative dose ≥300 mg/m2 of doxorubicin or ≥540 mg/m2 of epirubicin, and it is no more
2 contraindicated for children requiring chemotherapy with high cumulative dose (> 300 mg/m 2) of
3 doxorubicin or the equivalent dose of another anthracycline (24)
4 As showed in Table S1, several studies have suggested potential advantages for LVEF recovery and
5 cardioprotection associated with the use of BBs and RAAS inhibitors. Despite the positive findings, the

PT
6 significant heterogeneity between the studies is a significant limitation (25). Moreover, only a small
7 number of drugs in the studied pharmacological classes appear to have a significant cardioprotective
RI
8 effect. To date, only two clinical studies have examined the use of MRAs thus far, investigating the
9 effectiveness of spironolactone (26) and eplerenone (27) in preventing cardiotoxicity. The beneficial
SC
10 effects of statins in preventing HF in patients receiving anthracycline is being tested. Future research
11 should clarify the possible clinical relevance and applicability of therapies acting on pro-oxidant and
U
12 pro-inflammatory pathways specifically involved in cardiotoxicity (28).
13 Secondary prevention includes the use of medical therapies in patients who have developed a
14 N
cardiotoxic damage, possibly identified through imaging and/or biomarkers. According to the ESC
A
15 Position Paper (22), a cardioprotective strategy based on the administration of one or more guideline-
M
16 based HF treatments is advised in patients with a considerable drop in LVEF, especially if it is
17 accompanied by a shift in natriuretic peptides. In patients with subclinical heart injury, however, there
18 is no indication for any form of cardioprotective therapy. If heart failure occurs while receiving
D
19 chemotherapy, the patient should be managed in accordance with the most recent ESC
TE
20 recommendations for HF. According to the oncology team, stopping the medication until the patient
21 reaches clinical stability is advised if cardiotoxic treatment is interrupted.
EP
22
23 7. How can we predict outcome?
CC
24
25 Anthracycline-induced cardiomyopathy occurs in up to 10% of cancer survivors with 98% of cases
26 occurring within the first year of anthracycline exposure (22). An LVEF <40% in patients with severe
A
27 cardiotoxicity correlates with a 10-fold increase in total mortality, while there is no agreement on the
28 impact on mortality of LVEF values between 40-50% (29). A decline in LVEF, either symptomatic or
29 not, predicts a worse outcome: For example, at a 3.5-year follow-up, asymptomatic LVEF decline in
30 patients treated with anthracyclines is associated with increases in adverse cardiac events. (3). An early
31 treatment is more likely to induce LVEF recovery, which is associated with a reduction in adverse
32 cardiac events (30).
9
1 Patients experiencing a persistent increase in cTn during anti-cancer treatment have a higher risk of
2 subsequent LV dysfunction (3), and a prompt therapy with enalapril could change the natural
3 development of cardiotoxicity (31). Nevertheless, patients with abnormal biomarkers (cTn and NT-
4 proBNP) but LVEF ≥50% did not show a poor outcome (29).
5 Overall, the optimal use of imaging and laboratory techniques to predict outcomes remains to be

PT
6 defined.
7
RI
8 8. Which follow-up strategy should be pursued in long-term survivors?
9
SC
10 A consensus about long-term cardiomyopathy surveillance strategies for childhood cancer survivors
11 has stated that surveillance should start no later than 2 years following the end of cardiotoxic therapy
U
12 and be repeated every 5 years. (32).
13 In 2013, Carver et al. proposed a screening algorithm for asymptomatic adult cancer survivors,
14 N
based on 4 points: prior cancer therapy, risk factors (including age >65 years, female sex, obesity,
A
15 hypertension etc.), functional status at baseline and follow-up visits, and cardiac structure. All
M
16 survivors are recommended to undergo ECG, echocardiogram and BNP measurement at baseline. Even
17 if all 3 are normal, the patient is considered at risk of HF (stage A), and a re-evaluation every 2 years
18 with clinical history, physical examination and BNP measurement is recommended, as well as an
D
19 echocardiogram every 5 years. Patients with an abnormal echocardiogram at baseline are considered
TE
20 stage B, and re-evaluation every 6 months is advised (33).

21
EP
22 Nowadays, recommendations for after-anticancer therapy evaluations vary according to the single
23 patient (34). For asymptomatic patients who have normal cardiac function, periodic screening for the
CC
24 development of LV dysfunction should be considered at 6, 12 months and 2 years post-treatment and

25 periodically thereafter. For patients who developed asymptomatic LV dysfunction or HF, regular
26 cardiology evaluation should be continued indefinitely, regardless of the improvement in LVEF or the
A
27 presence of symptoms. Finally, for patients with a history of mediastinal chest radiotherapy, evaluation
28 for CAD and valvular disease is recommended, starting at 5 years post-treatment, and then every 3-5
29 years.
30
31
10
1 9. Which is the best treatment for cardiovascular risk factors and heart failure?
2
3 The use of BBs and/or an angiotensin antagonist for the treatment of arterial hypertension should be
4 preferred since these drugs have shown additional cardioprotective effect during anthracyclines and/or
5 trastuzumab treatment (35). A pre-existing diagnosis of HF does not necessarily exclude treatment with

PT
6 potential cardiotoxic anti-cancer therapies, but rather allocates the patient in a high-risk category
7 requiring cardioprotective treatment and close monitoring (36). Patients developing HF with reduced
RI
8 ejection fraction during or after anti-cancer treatment should receive standard HF care according to the
9 current guidelines (36). For patients with an important reduction of LVEF (<40%) and without at least
SC
10 partial recovery after cardioprotective therapy, continuation of anti-cancer therapies known to be
11 cardiotoxic is not recommended (6), unless there are no alternative anticancer treatment effective
U
12 options.
13 The best timing for the start of an early cardioprotective treatment should be evaluated based on
14 N
change in cardiac function, alteration of cardiac markers (cTn and NPs) and cardiovascular
A
15 comorbidities. Starting ACEi and BBs is highly suggested even in asymptomatic patients with an initial
M
16 alteration of myocardial deformation at speckle imaging or with a rise of cTn, even if LVEF is
17 preserved (34). Early ACEi initiation in patients with elevated cTnI prevents late development of
18 cardiomyopathy and HF (25).
D
19 Little is known about long-term outcomes and prognosis for cancer patients who have recovered from
TE
20 cardiac dysfunction, and the need for continuing HF medications after recovery. It is reasonable to
21 recommend to withdrawn HF therapy only after a period of stability, and in absence of other cardiac
EP
22 risk factors and ongoing anticancer therapy.

23
CC
24 10. How to manage atrial fibrillation in cancer patients?

25
26 Atrial fibrillation (AF) is common in patients with cancer (37), independently of the type of
A
27 malignancy (38), with an incidence of 17.4 per 1000 person-years versus 3.7 per 1000 person-years in
28 the general population (38).
29 The management of AF in cancer patients poses specific challenges; AF is per se a condition
30 favoring hypercoagulation within the heart, hence anticoagulation is mandatory in most cases (39).
31 Nonetheless, current guidelines do not provide clear-cut recommendations on the optimal thrombo-
32 prophylaxis strategy in cancer patients. Moreover, commonly employed scores to evaluate the balance
11
1 between thromboembolic and bleeding risks of AF (namely, CHA2DS2-VASc and HAS-BLED) have
2 not been validated in patients with cancer (22). Low molecular weight heparin (LMWH) is often
3 preferred over warfarin in cancer patients because of the risk for significant variations in the
4 international normalized ratio (39). As for non-vitamin K antagonist oral anticoagulants (NOACs), data
5 on their role in the prevention of AF-related stroke and systemic embolism are limited (40). A meta-

PT
6 analysis showed how the use of NOACs in patients with AF and cancer resulted in lower or similar
7 rates of thromboembolic and bleeding events compared to warfarin (41). However, caution should be
RI
8 taken when prescribing NOACs to patients undergoing chemotherapy, due to the possible occurrence
9 of drug-drug interactions with new anticancer treatments (40). Moreover, NOACs therapy should be
SC
10 reevaluated whenever a patient is scheduled for a cycle of myelosuppressive chemotherapy or
11 radiotherapy, given that they might determine a reduction in the platelet count, renal/liver function, and
U
12 vascular integrity.
13 As for medical management of AF in cancer patients, the ESC Position Paper on cancer treatments
14 N
and cardiovascular toxicity recommends an individualized approach regarding the choice between rate
A
15 or rhythm control (22). Rate control can be achieved with beta-blockers, non-dihydropyridine calcium
M
16 channel blockers, and, in selected cases, digitalis (especially in patients with HF) (22). Concerning
17 rhythm control, advances in ablation techniques and the introduction of new-generation catheters have
18 simplified percutaneous ablation procedures and extended their use to more complex scenarios. There
D
19 is initial evidence on the possibility of performing percutaneous pulmonary vein isolation in patients
TE
20 with active cancer or previous history of cancer, apparently showing good arrhythmia-free survival
21 rates, but with conflicting results in terms of safety, especially regarding the risk of periprocedural
EP
22 bleeding (42-45). Future large, dedicated studies should clarify whether percutaneous AF ablation is
23 associated with a prognostic and/or symptomatic benefit in cancer patients.
CC
24
25
26 Conclusion
A
27
28 Cardioncology is a relatively young and developing field of study; given the extensive overlap between
29 cancer and cardiovascular diseases, the management of the cancer patient receiving cardiotoxic
30 treatments is a particularly complicated and multifaceted subject. We attempted to give the physician
31 the skills they need to interact with the field of cardioncology by responding to 10 questions on the
32 subject of cardiotoxicity, ranging from the description of cardiotoxic damage to therapy and follow-up
12
1 measures in cancer survivors. The major crucial issues of cardiotoxicity detection, treatment, and
2 patient outcome are lacking clear data, necessitating additional research to support, enlarge, and
3 integrate the body of knowledge currently known about cardiology.
4
5

PT
6
7
RI
8
9
SC
10
11
U
12 Funding
13 The author(s) received no financial support for the research, authorship, and/or publication of this
14 article N
A
15
M
16 Declaration of conflicting interests
17 The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or
18 publication of this article.
D
19
TE
20 Author contribution
21 MC, IF, AF and DC, contributed to the conception of the review, the bibliographic research, and the
EP
22 drafting of the manuscript. AG, AA, CG, CP, VC, CP, FG, CCand ME contribuited to critical revision
23 and editing. MC designated tables and figures. All authors gave final approval and agreed to be
CC
24 accountable for all aspects of work ensuring integrity and accuracy.

25
26
A
27
28
29
30
31
32
13
1 References
2
3 1. Plana JC, Galderisi M, Barac A et al. Expert consensus for multimodality imaging evaluation of
4 adult patients during and after cancer therapy: a report from the American Society of
5 Echocardiography and the European Association of Cardiovascular Imaging. European Heart

PT
6 Journal - Cardiovascular Imaging 2014;15:1063–93.
7 2. Cardinale D, Colombo A, Torrisi R et al. Trastuzumab-Induced Cardiotoxicity: Clinical and
RI
8 Prognostic Implications of Troponin I Evaluation. JCO 2010;28:3910–6.
9 3. Cardinale D, Sandri MT, Colombo A et al. Prognostic Value of Troponin I in Cardiac Risk
SC
10 Stratification of Cancer Patients Undergoing High-Dose Chemotherapy. Circulation
11 2004;109:2749–54.
U
12 4. Herrmann J, Lenihan D, Armenian S et al. Defining cardiovascular toxicities of cancer
13
14
N
therapies: an International Cardio-Oncology Society (IC-OS) consensus statement. European
Heart Journal 2022;43:280–99.
A
15 5. Pareek N, Cevallos J, Moliner P et al. Activity and outcomes of a cardio‐oncology service in
M
16 the United Kingdom—a five‐year experience. Eur J Heart Fail 2018;20:1721–31.Herrmann J,

17 Lerman A, Sandhu NP et al. Evaluation and Management of Patients With Heart Disease and
D
18 Cancer: Cardio-Oncology. Mayo Clinic Proceedings 2014;89:1287–306.

TE
19 6. Herrmann J, Lerman A, Sandhu NP et al. Evaluation and Management of Patients With Heart
20 Disease and Cancer: Cardio-Oncology. Mayo Clinic Proceedings 2014;89:1287–306.
21 7. Bertero E, Canepa M, Maack C et al. Linking Heart Failure to Cancer: Background Evidence
EP
22 and Research Perspectives. Circulation 2018;138:735–42.

23 8. Pavo N, Raderer M, Hülsmann M et al. Cardiovascular biomarkers in patients with cancer and
CC
24 their association with all-cause mortality. Heart 2015;101:1874–80.

25 9. Boer RA, Meijers WC, Meer P et al. Cancer and heart disease: associations and relations. Eur J
A
26 Heart Fail 2019;21:1515–25.

27 10. Bertero E, Ameri P, Maack C et al. Bidirectional Relationship Between Cancer and Heart
28 Failure: Old and New Issues in Cardio-oncology. Card Fail Rev 2019;5:106–11.
29 11. Aimo A, Castiglione V, Borrelli C et al. Oxidative stress and inflammation in the evolution of
30 heart failure: From pathophysiology to therapeutic strategies. Eur J Prev Cardiolog
31 2020;27:494–510.
14
1 12. Coumbe BGT, Groarke JD. Cardiovascular Autonomic Dysfunction in Patients with Cancer.
2 Curr Cardiol Rep 2018;20:69.
3 13. Karlstaedt A, Zhang X, Vitrac H et al. Oncometabolite D -2-hydroxyglutarate impairs α-
4 ketoglutarate dehydrogenase and contractile function in rodent heart. Proc Natl Acad Sci USA
5 2016;113:10436–41.

PT
6 14. Tadic M, Genger M, Baudisch A et al. Left Ventricular Strain in Chemotherapy-Naive and
7 Radiotherapy-Naive Patients With Cancer. Canadian Journal of Cardiology 2018;34:281–7.
RI
8 15. Jones LW, Courneya KS, Mackey JR et al. Cardiopulmonary Function and Age-Related
9 Decline Across the Breast Cancer Survivorship Continuum. JCO 2012;30:2530–7.
SC
10 16. Thavendiranathan P, Negishi T, Somerset E et al. Strain-Guided Management of Potentially
11 Cardiotoxic Cancer Therapy. Journal of the American College of Cardiology 2021;77:392–401.
U
12 17. Ananthan K, Lyon AR. The Role of Biomarkers in Cardio-Oncology. J of Cardiovasc Trans Res
13 2020;13:431–50.
14
N
18. Tan L-L, Lyon AR. Role of Biomarkers in Prediction of Cardiotoxicity During Cancer
A
15 Treatment. Curr Treat Options Cardio Med 2018;20:55.
M
16 19. Pudil R, Mueller C, Čelutkienė J et al. Role of serum biomarkers in cancer patients receiving
17 cardiotoxic cancer therapies: a position statement from the CARDIO‐ONCOLOGY STUDY GROUP of
D
18 the HEART FAILURE ASSOCIATION and the CARDIO‐ONCOLOGY COUNCIL OF THE EUROPEAN
TE
19 SOCIETY OF CARDIOLOGY. Eur J Heart Fail 2020;22:1966–83.
20 20. Pituskin E, Mackey JR, Koshman S et al. Multidisciplinary Approach to Novel Therapies in
EP
21 Cardio-Oncology Research (MANTICORE 101–Breast): A Randomized Trial for the

22 Prevention of Trastuzumab-Associated Cardiotoxicity. JCO 2017;35:870–7.
CC
23 21. Sawaya H, Sebag IA, Plana JC et al. Assessment of Echocardiography and Biomarkers for the
24 Extended Prediction of Cardiotoxicity in Patients Treated With Anthracyclines, Taxanes, and
25 Trastuzumab. Circ: Cardiovascular Imaging 2012;5:596–603.
A
26 22. Zamorano JL, Lancellotti P, Rodriguez Muñoz D et al. 2016 ESC Position Paper on cancer
27 treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for
28 Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the
29 European Society of Cardiology (ESC). Eur Heart J 2016;37:2768–801.
30 23. Menna P, Salvatorelli E. Primary Prevention Strategies for Anthracycline Cardiotoxicity: A
31 Brief Overview. Chemotherapy 2017;62:159–68.
15
1
2 24. Macedo AVS, Hajjar LA, Lyon AR et al. Efficacy of Dexrazoxane in Preventing Anthracycline
3 Cardiotoxicity in Breast Cancer. JACC: CardioOncology 2019;1:68–79.
4 25. Lewinter C, Nielsen TH, Edfors LR et al. A systematic review and meta-analysis of beta-
5 blockers and renin–angiotensin system inhibitors for preventing left ventricular dysfunction due

PT
6 to anthracyclines or trastuzumab in patients with breast cancer. European Heart Journal
7 2021:ehab843.
RI
8 26. Akpek M, Ozdogru I, Sahin O et al. Protective effects of spironolactone against anthracycline-
9 induced cardiomyopathy: Effects of spironolactone on anthracycline cardiomyopathy. Eur J
SC
10 Heart Fail 2015;17:81–9.
11 27. Davis MK, Villa D, Tsang TSM et al. Effect of Eplerenone on Diastolic Function in Women
U
12 Receiving Anthracycline-Based Chemotherapy for Breast Cancer. JACC: CardioOncology
13
14
2019;1:295–8.
N
28. Fabiani I, Aimo A, Grigoratos C et al. Oxidative stress and inflammation: determinants of
A
15 anthracycline cardiotoxicity and possible therapeutic targets. Heart Fail Rev 2021;26:881–90.
M
16 29. López-Sendón J, Álvarez-Ortega C, Zamora Auñon P et al. Classification, prevalence, and

17 outcomes of anticancer therapy-induced cardiotoxicity: the CARDIOTOX registry. European
D
18 Heart Journal 2020;41:1720–9.

TE
19 30. Cardinale D, Colombo A, Lamantia G et al. Anthracycline-Induced Cardiomyopathy. Journal

20 of the American College of Cardiology 2010;55:213–20.
EP
21 31. Cardinale D, Ciceri F, Latini R et al. Anthracycline-induced cardiotoxicity: A multicenter

22 randomised trial comparing two strategies for guiding prevention with enalapril: The
CC
23 International CardioOncology Society-one trial. European Journal of Cancer 2018;94:126–3
24 32. Armenian SH, Hudson MM, Mulder RL et al. Recommendations for cardiomyopathy
25 surveillance for survivors of childhood cancer: a report from the International Late Effects of
A
26 Childhood Cancer Guideline Harmonization Group. The Lancet Oncology 2015;16:e123–36.

27 33. Carver JR, Szalda D, Ky B. Asymptomatic Cardiac Toxicity in Long-Term Cancer Survivors:
28 Defining the Population and Recommendations for Surveillance. Seminars in Oncology
29 2013;40:229–38.
30 34. Curigliano G, Lenihan D, Fradley M et al. Management of cardiac disease in cancer patients
31 throughout oncological treatment: ESMO consensus recommendations. Annals of Oncology
16
1 2020;31:171–90.
2 35. Guglin M, Krischer J, Tamura R et al. Randomized Trial of Lisinopril Versus Carvedilol to
3 Prevent Trastuzumab Cardiotoxicity in Patients With Breast Cancer. Journal of the American
4 College of Cardiology 2019;73:2859–68.
5 36. Broberg AM, Geisler J, Tuohinen S et al. Prevention, Detection, and Management of Heart

PT
6 Failure in Patients Treated for Breast Cancer. Curr Heart Fail Rep 2020;17:397–408.
7 37. Menichelli D, Vicario T, Ameri P et al. Cancer and atrial fibrillation: Epidemiology,
RI
8 mechanisms, and anticoagulation treatment. Progress in Cardiovascular Diseases 2021;66:28–
9 36.
SC
10 38. Jakobsen CB, Lamberts M, Carlson N et al. Incidence of atrial fibrillation in different major
11 cancer subtypes: a Nationwide population-based 12 year follow up study. BMC Cancer
U
12 2019;19:1105.
13 N
39. Farmakis D, Parissis J, Filippatos G. Insights Into Onco-Cardiology. Journal of the American
A
14 College of Cardiology 2014;63:945–53.
M
15 40. Conen D, Wong JA, Sandhu RK et al. Risk of Malignant Cancer Among Women With New-
16 Onset Atrial Fibrillation. JAMA Cardiol 2016;1:389.
D
17 41. Deng Y, Tong Y, Deng Y et al. Non–Vitamin K Antagonist Oral Anticoagulants Versus
TE
18 Warfarin in Patients With Cancer and Atrial Fibrillation: A Systematic Review and Meta‐
19 Analysis. JAHA 2019;8:e012540.
EP
20 42. Eitel C, Sciacca V, Bartels N et al. Safety and Efficacy of Cryoballoon Based Pulmonary Vein
21 Isolation in Patients with Atrial Fibrillation and a History of Cancer. JCM 2021;10:3669.
CC
22 43. Giustozzi M, Ali H, Reboldi G et al. Safety of catheter ablation of atrial fibrillation in cancer
23 survivors. J Interv Card Electrophysiol 2021;60:419–26.
A
24 44. Shabtaie SA, Luis SA, Ward RC et al. Catheter Ablation in Patients With Neuroendocrine
25 (Carcinoid) Tumors and Carcinoid Heart Disease. JACC: Clinical Electrophysiology
26 2021;7:151–60.
17
1 45. Kanmanthareddy A, Vallakati A, Reddy Yeruva M et al. Pulmonary Vein Isolation for Atrial
2 Fibrillation in the Postpneumonectomy Population: A Feasibility, Safety, and Outcomes Study:
3 AF Ablation in Pulmonary Vein Stumps. J Cardiovasc Electrophysiol 2015;26:385–9.

PT
5
RI
SC
U
N
A
M
D
TE
EP
CC
A
18
1
2 Table 1
3 old and new classification of cardiotoxicity (2,4,5)

5 Type of damage onset clinical manifestation reversibility dose correletion
PT
6 Acute cardiotoxicity
7 Within 2 weeks ↓myocardial contractility Usually Unknow
RI
8 after reversible
9 chemotherapy
SC
10
11 Early-onset chronic cardiotoxicity
U
12 Within 1 year dilated-hypokinetic Usually dose dependent
13 after cardiomyopathy irreversible
14 chemotherapy
N
A
15
16
M
17 Late-onset chronic cardiotoxicity

D
18 >1 year dilated-hypokinetic Usually dose dependent

19 after cardiomyopathy irreversible
TE
20 chemotherapy
21
22
EP
23
24
CC
25
26 Type of damage imaging biomarker symptomatic

A
27 Royal Brompton Hospital classification
28 Early biochemical normal ↑ BNP/cTn no cardiotoxicity
29 Early functional ↓ GLS*/ III–IV diastolic normal no

30 cardiotoxicity dysfunction
31 Early mixed ↓ GLS/III–IV diastolic ↑ BNP/cTn no

32 cardiotoxicity dysfunction
19
1 Symptomatic HF ↓ GLS/ III–IV diastolic ↑ BNP/cTn yes with
2 preserved EF dysfunction
3 Asymptomatic LVD ↓LVEF <50% ↑ BNP/cTn no

4 ↓LVEF >10%
5 to an LVEF <55%

6 Symptomatic LVD ↓LVEF <50% ↑ BNP/cTn yes
PT
7 ↓LVEF >10%
8 to an LVEF <55%
RI
9 IC-OS 2021 consensus
10 Asymptomatic CTRCD
SC
11
12 Mild ↓LVEF ≥ 50% and/or ↑ BNP/cTn no

13 ↓GLS* >15%
U
14
15 Moderate ↓LVEF ≥10% and/or N

↑ BNP/cTn no
A
16 to an LVEF of 40-
17 49%
M
18 ↓LVEF <10% to
19 an LVEF of 40-
20 49% and
D
21 ↓GLS >15%
TE
22
23 Severe ↓LVEF < 40% no

EP
24
25 Symptomatic CTRCD
CC
26
27 Mild ↓LVEF ≥ 50% and/or ↑ BNP/cTn mild HF symptoms,

28 ↓GLS >15% no intensification of
A
29 therapy required
30
31 Moderate ↓LVEF ≥10% and/or ↑ BNP/cTn moderate symptoms

32 to an LVEF of need for and intensification
33 40-49% of diuretic and HF therapy
34 ↓LVEF <10% to
35 an LVEF of 40-
20
1 49% and
2 ↓GLS >15%
4 Severe ↓LVEF < 40% The extent of symptoms

5 requires hospitalisation for

6 HF
PT
7
8 Very severe Requiring inotropic support,
RI
9 mechanical circulatory support
10 or consideration for
SC
11 transplantation
12
13
U
14
15
16
N
A
17 * the decrease in GLS is considered in absolute values
M
18
19 BNP: Brain natriuretic peptide; cTn: cardiac troponin; GLS: global longitudinal strain; LVEF: Left
D
20 ventricular ejection fraction;

TE
21
22
EP
23
24
CC
25
26
27
A
28
29
30
31
32
33
21
1 Table 2
2 Main biomarkers used for early detection of cardiotoxicity and under investigation (18,19)
Circulating biomarkers cut-off advantage disadvantage

PT
4 Troponin
5
RI
6  Conventional • ≥80 ng/L • Widespread and • Unknown optimal
7 troponin I and T • ≥30 ng/L cost-effective timing
SC
8 • No optimal
9 • Commonly studied threshold for risk
10 stratification
11
U
12 • Possibly predictive • No sure associations
13 of a future decline with cardiotoxicity risk
14
15
N
in LVEF
• Influence of renal function
A
16
17
M
18  High-sensitive • absolute δ • More sensible • Less specific

19 troponin I and T 7-9,2 ng/L
20 • Possibly detection • higher rate of false
D
21 of acute cardiotoxicity positives

22
TE
23 • discrepancies between
24 different assay platforms
EP
25 Natriuretic peptides
26

CC
27 BNP • 100 pg/mL * • Widely available • Unknown optimal

28 timing
29 • Gold-standard for • No optimal
30 clinical HF threshold for risk
A
31 stratification
32  NT-proBNP • 125 pg/mL * • Potential indicators • No sure associations

33 of late cardiotoxicity with cardiotoxicity risk
34
35 Biomarkers under
36 investigation
22
1
2  Galactin-3 • No significant
3 association with
4 cardiotoxicity
5  ST-2 • No sufficient data
6

 • Possibly detection • Need for
PT
7 GDF-15
8 of late anthracycline further studies
9 cardiotoxicity in pediatric
10 cancer survivors
RI
11
12
13
SC
14  CRP • ≥ 3 mg/L • Possibly use with • Poor specifity
15 T cell therapies (CAR)
16
U
17 • No significant
18 association with
19
20 N cardiotoxicity
A
21  MicroRNA • Up regulation • Present in multiple • Expensive
22 (miR-1 miR- 133 compared to body fluids
M
23 miR-208 baseline
24 miR-499) • Remain stable under • Not widespread
25 extreme temperatures
D
26 and pH • Needs further study

27
TE
28 • Have long half-life

29
30 • Can be measured
EP
31 using different methods

32 • More sensitive than TnI
33 for predicting the risk of
34 cardiotoxicity
CC
35
36  MPO • Rise in MPO • Associated with risk of • Limited data
37 levels from anthracycline and
A
38 baseline to trastuzumab cardiotoxicity • Sensitive to

39 ≥3 months processing
40 condition
41 • predictive of increased
42 cardiotoxicity risk over the
43 end of treatment
44
45
23
1
2 BNP: Brain natriuretic peptide; CRP: C-reactive protein; GDF-15: Growth differentiation factor-15;
3 PO: Myeloperoxidase; NT-proBNP: N-terminal pro brain-type natriuretic peptide.
4 *BNP and NT-pro-BNP levels are significantly higher in atrial fibrillation patients compared to the
5 rest of the general population.

PT
6
7
RI
8
9
SC
10
11
12
U
13
14 N
Table 3
A
15 primary prevention strategies suggested by ESC (23)
16
M
Chemotherapy Potential cardioprotective Clinical benefit Disadvantages/limitations

drug cardioprotective mechanism
D
measure
any type of treatment of reduced cardiac Reduced None
TE
chemotherapeutic cardiovascular stress incidence of HF

drug risk factors
Correction of Reduced cardiac Reduced none
comorbidities stress incidence of HF
EP
Anthracyclines Liposomal limited trans- Does not high costs

formulations endothelial cardiac change the
diffusion of the drug effectiveness of
CC
the drug
increased
cardiac
A
tolerance
continuous reduction of the maintenance of Prolonged hospitalisation
infusions maximum blood drug activity lack of long-term
concentration of the protection in some
drug (Cmax) reduced paediatric settings
exposure of the
heart to
anthracyclines
use less reduction of ROS reduced not definitely proven*
24
cardiotoxic production and incidence of HF
analogues, and oxidative stress
respect intensity
cumulative dose
limits
Dexrazoxane Iron chelation Reduced risk of reduces the efficacy of
enhances the profile HF anthracyclines

PT
of oxidative stress
inhibition of Well-tolerate
cardiomyocyte
apoptosis by
RI
hindering the
binding of
SC
anthracyclines to
topoisomerase IIβ
U
2
3 *about the use of less cardiotoxic analogues N

A
4
5
M
D
TE
EP
CC
A
25
26
PT
RI
SC
U
N
254x178 mm ( x DPI)
Grapahical Abstrat
A
M
D
TE
EP
CC
A
1
2
3

Accepted Manuscript: Management and Treatment of Cardiotoxicity Due To Anticancer Drugs: 10 Questions and Answers

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Accepted Manuscript: Management and Treatment of Cardiotoxicity Due To Anticancer Drugs: 10 Questions and Answers

Uploaded by

Copyright:

Available Formats

1 Management and treatment of cardiotoxicity due to anticancer drugs: 10 questions and answers

Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac170/6658185 by guest on 09 August 2022

14 Short title: 10 questions in cardioncology N

17 Address for correspondence:

20 Fondazione Toscana Gabriele Monasterio

22 E-Mail address: iacopofabiani@gmail.com -Phone: 050-3152216- Fax: 050-3153229

Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac170/6658185 by guest on 09 August 2022

17 treatment and surveillance of cancer patients under chemotherapy.

18 Keywords: cardiotoxic; cardiac biomarker; ventricular function; chemotherapy; cardio protection;

Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac170/6658185 by guest on 09 August 2022

22 and prevention to their patients.

24 1. How is cardiotoxicity defined and classified?

Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac170/6658185 by guest on 09 August 2022

Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac170/6658185 by guest on 09 August 2022

Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac170/6658185 by guest on 09 August 2022

20 capacity with a marked reduction in peak oxygen consumption (15).

24 chemotherapy, possibly using cardiac biomarkers or CMR.

27 5a. Which are the imaging techniques used to study cardiotoxicity?

Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac170/6658185 by guest on 09 August 2022

Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac170/6658185 by guest on 09 August 2022

Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac170/6658185 by guest on 09 August 2022

Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac170/6658185 by guest on 09 August 2022

20 stage B, and re-evaluation every 6 months is advised (33).

24 development of LV dysfunction should be considered at 6, 12 months and 2 years post-treatment and

Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac170/6658185 by guest on 09 August 2022

22 risk factors and ongoing anticancer therapy.

24 10. How to manage atrial fibrillation in cancer patients?

Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac170/6658185 by guest on 09 August 2022

Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac170/6658185 by guest on 09 August 2022

24 accountable for all aspects of work ensuring integrity and accuracy.

Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac170/6658185 by guest on 09 August 2022

7 2. Cardinale D, Colombo A, Torrisi R et al. Trastuzumab-Induced Cardiotoxicity: Clinical and

16 the United Kingdom—a five‐year experience. Eur J Heart Fail 2018;20:1721–31.Herrmann J,

18 Cancer: Cardio-Oncology. Mayo Clinic Proceedings 2014;89:1287–306.

22 and Research Perspectives. Circulation 2018;138:735–42.

24 their association with all-cause mortality. Heart 2015;101:1874–80.

26 Heart Fail 2019;21:1515–25.

Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac170/6658185 by guest on 09 August 2022

19 SOCIETY OF CARDIOLOGY. Eur J Heart Fail 2020;22:1966–83.

21 Cardio-Oncology Research (MANTICORE 101–Breast): A Randomized Trial for the

Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac170/6658185 by guest on 09 August 2022

16 29. López-Sendón J, Álvarez-Ortega C, Zamora Auñon P et al. Classification, prevalence, and

18 Heart Journal 2020;41:1720–9.

19 30. Cardinale D, Colombo A, Lamantia G et al. Anthracycline-Induced Cardiomyopathy. Journal

21 31. Cardinale D, Ciceri F, Latini R et al. Anthracycline-induced cardiotoxicity: A multicenter

23 International CardioOncology Society-one trial. European Journal of Cancer 2018;94:126–3

26 Childhood Cancer Guideline Harmonization Group. The Lancet Oncology 2015;16:e123–36.

Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac170/6658185 by guest on 09 August 2022

Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac170/6658185 by guest on 09 August 2022

3 old and new classification of cardiotoxicity (2,4,5)

Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac170/6658185 by guest on 09 August 2022

7 Within 2 weeks ↓myocardial contractility Usually Unknow

11 Early-onset chronic cardiotoxicity

17 Late-onset chronic cardiotoxicity

18 >1 year dilated-hypokinetic Usually dose dependent

26 Type of damage imaging biomarker symptomatic

27 Royal Brompton Hospital classification

28 Early biochemical normal ↑ BNP/cTn no cardiotoxicity

29 Early functional ↓ GLS*/ III–IV diastolic normal no

31 Early mixed ↓ GLS/III–IV diastolic ↑ BNP/cTn no

3 Asymptomatic LVD ↓LVEF <50% ↑ BNP/cTn no

Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac170/6658185 by guest on 09 August 2022

12 Mild ↓LVEF ≥ 50% and/or ↑ BNP/cTn no