Cardio-Oncology: Approach to the Patient

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Never in history have there been more cancer survivors than presently, and thus, never have the chances been greater for a cardiologist to treat a patient with a cancer diagnosis. The latter conclusion holds true even more so in view of the general aging of the population and the fact that aging is a risk factor for both cancer and cardiovascular diseases (CVD). ^, The same applies to obesity, and a sedentary lifestyle and smoking add to the list of factors that increase the risk not only for CVD but also cancer. Thus, the cancer patient of today often presents with cardiovascular (CV) risk factors and diseases that require optimal management, in particular as they can complicate cancer care. Furthermore, cancer therapy can cause CVD, as outlined in Chapter 56 , with significant implications for morbidity and mortality. Indeed, cancer patients with CVD, either present before or developing during cancer therapy, have worse overall survival, emphasizing the call for the optimal management of both. This call extends to all cardiologists, who need to have a basic understanding of how to approach CVD in the cancer patient, as well as those who specialize in this area that has become known as cardio-oncology.

One intuitive and practical approach to the cancer patient with CVD can be summarized under the acronym SCI-FI (CV S ubject, Oncology C ontext, Cardio-Oncology I nteraction, and F ollow-up on I ntervention, Fig. 57.1 ). It begins with the CV issue in question, then takes the oncology/hematology context into consideration, and finally integrates these entities. The three CVD groups to be attentive to in particular are cardiomyopathy/heart failure (HF), vascular disease, and arrhythmias. These compose most of the referrals and can lead to fatal outcomes if not recognized and managed appropriately. Last but not least, the specific management aspects of these CVD vary by stage of presentation in the continuum of cancer care: before, during, or after cancer therapy ( Fig. 57.2 ). This chapter will follow this framework.

Approach to the Cancer Patient at Risk of or with Cardiovascular Diseases Before Cancer Therapy

Patients who were diagnosed with cancer and are about to undergo oncological or hematological treatment are referred for a cardiology consultation most commonly out of concern that the presence or risk of CVD could pose a threat to the completion of cancer therapy and the patient. A comprehensive understanding of CVD, as well as cancer, its treatment, and how it affects the CV system is needed to address such referrals. A conceptual model that provides a useful foundation and can almost universally be applied is the multiple-hit model ( Fig. 57.3 ). The key concept is that injuries from cancer therapies add to any pre-existing impairment of CV function decreasing the CV reserve to the point of its exhaustion and eventually the clinical appearance of disease states. Very pertinent questions for any patient who is to undergo cancer therapy with concerns for CVD are: how much of the CV reserve is left, what is the margin for toxicities, and what is to be expected? Aligned with this basic concept, applicable consensus documents and guidelines are in general agreement that all cancer patients who are about to start any (potentially) cardiotoxic therapy should have a baseline assessment of cardiac function, with echocardiography as the preferred imaging modality, an assessment of any potential CVD and CV risk factors, and optimal control of any of the CV abnormalities identified.

FIGURE 57.3, Multiple-hit model for cardio-oncology. In most cancer patients a number of factors (or “hits”) lead to the clinical emergence of cardiovascular disease (CVD). Many patients already have cardiovascular risk factors or (subclinical) CVD that lower the reserve to tolerate additional stressors such as cancer and cancer therapy. Lifestyle factors and genetics further influence the equation.

Cardiomyopathy/Heart Failure Considerations

Cardiotoxicity has historically received the greatest interest and over the years has been defined by many different criteria (see also Chapter 56 ). Moreso, two subtypes had been proposed on the basis of the cardiotoxicity reversibility pattern (irreversible cardiac injury, or type 1, and reversible cardiac dysfunction, or type 2), and the 2014 American Society of Echocardiography (ASE)/European Association of Cardiovascular Imaging (EACI) consensus document assigned all (potentially) cardiotoxic medication to one of these two groups. This model even set the tone for pre-, on-, and posttreatment evaluations. However, recent data have challenged this concept and indicate that breast cancer patients who experienced trastuzumab cardiotoxicity have an impaired CV function even years later. Furthermore, improvement in cardiac function may be seen even in patients with anthracycline cardiotoxicity. ^, Alternative classification systems have been proposed, and in the general approach to cancer patients at risk of cardiac dysfunction it might be useful to consider the mechanisms that can account for the decrease in cardiac function: (1) directly harmful effects on the myocardium, (2) indirectly harmful effects on the myocardium, for example, via progression of coronary artery disease (CAD), ischemia, metabolic derangement, and (3) mediated by inflammation ( Table 57.1 ). Such an approach directs to optimal treatment strategies, for example, neurohormonal blockade in case of cardiomyopathy versus improvement in coronary blood flow in case of CAD or coronary vasospasm versus anti-inflammatory in case of myocarditis. For preventive efforts and screening recommendations for cardiomyopathy see supplementary text online.

Radiation-induced heart disease involves every structure of the heart and can lead to restrictive cardiomyopathy, constrictive pericarditis, valvular heart disease, and conduction and autonomic function abnormalities (see also Chapter 56 ). ^, Every patient undergoing chest and/or neck radiation therapy should therefore be carefully counseled. Patients with a history of CAD and myocardial infarction (MI) in particular should be informed about the risks and benefits of undergoing chest radiation therapy. An increased risk of acute coronary events was seen in particular in this subgroup of women who underwent radiation therapy for breast cancer. The risk of these events is not immediate but within the timeline of years. Time to onset of cardiomyopathy is usually beyond 10 years and classically presents as restrictive cardiomyopathy and HF with preserved ejection fraction. Reduction of dose exposure is the best preventive strategy and several techniques are available. Anti-inflammatory and antioxidant therapies including statins and angiotensin converting enzyme (ACE) inhibitors are theoretically attractive but have not been proven beneficial in clinical practice.

TABLE 57.1

Overview of the Three Principal Presentations of Cardiotoxicity with Cancer Therapy

From Herrmann J. Adverse cardiac effects of cancer therapies: cardiotoxicity and arrhythmia. Nat Rev Cardiol . 2020;17:474–502.

	Categories of Cancer Therapy-Related Cardiotoxicities
	Direct Impairing Effect on the Myocardium	Indirect Impairing Effect on the Myocardium	Impairing Effect Owing to Myocarditis
Risk with Cancer Therapy
Doxorubicin	+	+	+ (toxic or reactive)
Cyclophosphamide	+	+	+ (toxic or reactive)
5-Fluorouracil	+	+	NR
HER2 inhibitors	+	Inconclusive findings	NR
VEGF inhibitors	+ (TKIs)	+	NR
Immune checkpoint inhibitors	Inconclusive findings	+	+ (immune-mediated)
Radiation therapy	+ (at high dose)	+	+ (toxic or reactive)
Diagnosis
Imaging	Echocardiogram Cardiac MRI MUGA scan	(Stress) echocardiogram (Stress) cardiac MRI Stress Sestamibi–PET CT coronary angiogram Vasoreactivity studies	Cardiac MRI PET Echocardiogram
Biomarkers	Cardiac troponins Natriuretic peptides (especially chronically)	Thyroid function studies Cytokines Catecholamines	Cardiac troponins Natriuretic peptides
Management
Treatment	Stop cancer therapy Beta-blocker (carvedilol and nebivolol) ACE inhibitor ARB Spironolactone	Stop cancer therapy Therapy directed to the underlying cause (e.g., correction of myocardial ischemia or valve disease)	Stop cancer therapy For ICI: anti-inflammatory or immunosuppressive therapy, supportive care (e.g., ECMO)
Prevention	Screening for comorbidities For anthracyclines: cardiovascular medications (as above) Exercise	Screening for predisposing conditions For radiation therapy: dose reduction, for example by shielding, positioning or proton beam Dose and type of administration of cancer therapeutics	Screening for comorbidities (efficacy not proven) Early detection with biomarkers and/or ECG changes (heart blocks, ventricular arrhythmias including ectopy and tachycardia, atrial fibrillation)

ACE , Angiotensin converting enzyme; ARB , angiotensin receptor blocker; CT , computed tomography; ECMO , extracorporeal membrane oxygenation; ICI , immune checkpoint inhibitor; MRI , magnetic resonance imaging; MUGA , multigated acquisition scan; NR , not reported; PET , positron emission tomography; TKI , tyrosine kinase inhibitors; VEGF , vascular endothelial growth factor.

Vascular Disease Considerations

In addition to the historically well-known increased risk of venous thromboembolism (VTE), cancer patients can present with typical and atypical chest pain episodes, MI, transient ischemic attack, stroke, claudication, critical limb ischemia, and Raynaud’s. Based on pathophysiology, one may propose three main vascular toxicity types: acute thrombosis, acute vasospasm, and accelerated atherosclerosis ( Table 57.2 ).

TABLE 57.2

Overview of the Three Principal Presentations of Arterial Vascular Toxicity with Cancer Therapy

From Herrmann J. Vascular toxic effects of cancer therapies. Nat Rev Cardiol . 2020;17:503–522.

Presentation	Acute Vasospasm	Acute Thrombosis	Accelerated Atherosclerosis

Onset after cancer therapy	Days to weeks	Weeks to months	Months to years
Reversibility	Very likely	Likely	Very unlikely
Examples of cancer therapeutics	5-fluorouracil, capecitabine, platinum drugs, VEGF inhibitors	Platinum drugs, bleomycin, vinca alkaloids, VEGF inhibitors, ICIs	Nilotinib, ponatinib, cisplatin, VEGF inhibitors
Treatment	Nitrates, calcium-channel blocker (CCB)	Thrombectomy with/without PTCA, stent, DAPT, statin therapy	Revascularization, aspirin, statin, amlodipine, ACE-inhibitor, exercise
On-therapy screening	Signs and symptoms	Signs and symptoms	Signs and symptoms
Prevention	Vasoreactivity studies, ECG (ST-segment elevation monitoring	vWF levels, circulating endothelial cell and/or endothelial progenitor cell levels	Ankle–brachial index, cardiac stress test, coronary CT angiography

ACE , angiotensin-converting enzyme; ASCDV , atherosclerotic cardiovascular disease; CCB , calcium channel blockers; CT , computed tomography; CVD , cardiovascular disease; DAPT , dual antiplatelet therapy; ECG , electrocardiogram; ICI , immune checkpoint inhibitor; PTCA , percutaneous transluminal coronary angioplasty; VEGF , vascular endothelial growth factor; vWF, von Willebrand factor.

The risk of venous thrombosis in cancer patients relates not to a single but several factors (patient-, cancer-, and treatment-related). These are captured in risk prediction models such as the most widely used Khorana risk score. Based on data indicating a 60% reduction in VTE and/or VTE-related deaths, practice guidelines of various societies suggest the use of direct oral anticoagulants (DOACs) as primary thromboprophylaxis in ambulatory cancer patients who are about to start chemotherapy and have a Khorana score ≥2, if there are no drug-drug interactions and no high-risk scenario for bleeding. Low-molecular-weight heparin (LMWH) remains an option for outpatient thromboprophylaxis in high-risk patients. For patients with multiple myeloma receiving “IMiD”-based combination therapy, current guidelines recommend aspirin 81 to 325 mg daily if none or only one individual/myeloma risk factor, otherwise LMWH equivalent to 40 mg enoxaparin daily or full-dose warfarin. In hospitalized patients with major surgery or acute medical illness, thromboprophylaxis with heparin or LMWH is recommended per standard recommendations with consideration for 4 weeks extension in high-risk post-operative patients in the setting of abdominal and pelvic surgery for malignancy.

Regarding arterial thromboembolic events (ATEs), the highest risk period is within 1 month before and after cancer diagnosis, thereafter declining by persisting for at least 12 months. ^, Advanced (stage 3 and 4) cancers and those of the gastrointestinal tract and the lung pose the highest malignancy-related risk categories for ATEs, similar to VTE. A therapy-related risk of ATEs is seen in particular with vascular endothelial growth factor (VEGF) inhibitors and platinum drugs.

Acute vasospasm should be anticipated for patients to be started on 5-fluorouracil (5-FU), capecitabine, paclitaxel, cisplatin, bleomycin, VEGF inhibitors such as sorafenib, and Bcr-Abl inhibitors such as dasatinib. Risk factors for 5-FU cardiotoxicity have variably been described but likely a history of cardiac disease (in particular ischemic heart disease [IHD]) and especially MI is relevant. Furthermore, smoking is likely of significance for peripheral vasoconstriction. Accelerated atherosclerosis in cancer patients is most commonly associated with radiation therapy but has received attention with the use of Bcr-Abl inhibitors such as nilotinib and ponatinib in recent years; it may also be seen with VEGF inhibitors and cisplatin. For preventive efforts and screening recommendations for cardiovascular disease see supplementary text online.

Arrhythmia Considerations

Patients with cancer who have electrocardiogram (ECG) abnormalities, impaired exercise capacity, or CVD at baseline should be assumed to be more susceptible to cancer therapy-induced arrhythmias, as are those undergoing treatment regimens with known cardiotoxicity potential. Therefore, as a general rule, comorbidities that could represent a possible arrhythmogenic substrate should be identified and treated aggressively before and during cancer therapy. Early identification and appropriate management of cardiac ischemia, dysfunction, and remodeling is also likely to be the best strategy to modulate the arrhythmogenic substrate and improve outcomes in patients with cancer therapy-induced arrhythmias. These recommendations hold true for QTc prolongation and related ventricular arrhythmias.

Crizotinib, dasatinib, lapatinib, nilotinib, pazopanib, sorafenib, sunitinib, vandetanib, and vemurafenib should be administered with caution in patients with pre-existing QTc prolongation or QTc-prolongation-related risk factors. As illustrated for several tyrosine kinase inhibitors (TKIs), such as vandetanib, electrolytes should be corrected before initiation of cancer therapy (goal value for serum K ⁺ levels ≥4 mEq/L and for magnesium and calcium within normal limits) and monitored along with ECGs, as outlined above (at baseline, at 2 to 4 weeks, at 8 to 12 weeks, and every 3 months thereafter). The common cutoffs for the QTc interval are 450 msec before and 500 msec during therapy (the one exception being nilotinib 480 msec). Full-dose therapy can be given if the QTc is less than 450 msec, half-dose if between 450 and upper limit, no dose if above the upper limit.

The other common reason for referral is atrial fibrillation (AF), more commonly pre-existing though some cancer populations and therapeutics have been recognized as being more predisposed. The impact in terms of morbidity and mortality is the same and the approach to these patients should be the same as in the general population. For additional discussion on the management of AF see supplemental text online.

Approach to the Cancer Patient at Risk of or with Cardiovascular Diseases During Cancer Therapy

Patients are referred for a cardiology evaluation during active cancer treatment most commonly to seek guidance on how a noted CVD issue could be managed, its causal relationship with cancer therapy, and its overall impact on the patient’s cancer treatment plan. Such management decisions and judgment calls are among the most challenging given the unique characteristics and comorbidities of patients with active cancer, demanding a broader knowledge and experience with their trajectory. Standard practice guidelines written for the general population may need to be modified, although for the most part these should be followed and translate into better clinical outcomes. Pertinent societal recommendations and considerations for cancer patients with CVD presentations are covered elsewhere. ^, The 2020 European Society of Medicine Oncology (ESMO) recommendations for management of cardiac disease in cancer patients are outlined in eTable 57.1 .

ETABLE 57.1

2020 ESMO Consensus Recommendations for the Management of Cardiac Disease in Cancer Patients Throughout Oncologic Treatment

From Curigliano G, Lenihan D, Fradley M, et al. Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations. Ann Oncol . 2020;31(2):171–190.

Section	Recommendations
1. General principles	1.1. Screening for known CV risk factors in patients with cancer is recommended; treatment of identified CV risk factors according to current guidelines is recommended (LOE: I, GOR: A). 1.2. Many types of cancer therapy, especially mediastinal and left-sided chest radiation and certain chemotherapy and targeted agents can substantially affect the heart and vascular system and it is recommended that CV safety be monitored (LOE: I, GOR: A). 1.3. Close and early collaboration between cardiologists, oncologists, hematologists, and radiation oncologists is recommended to ensure lifelong CV health and to avoid unnecessary discontinuation of cancer therapy (LOE: III, GOR: C).
2. Before cancer treatment: Screening	2.1. Routine use of cardiac biomarkers (cardiac troponins [TnI or TnT], brain natriuretic peptide [BNP], or N-terminal pro-BNP) for patients undergoing potentially cardiotoxic chemotherapy is not well established. However, for high-risk patients (with pre-existing significant CVD) and those receiving high doses of cardiotoxic chemotherapy such as anthracycline, baseline measurement of such cardiac biomarkers should be considered (LOE: III, GOR: A). 2.2. For patients with a cancer diagnosis that requires treatment with a potentially cardiotoxic treatment, a baseline electrocardiogram (ECG), including measurement of a heart-rate corrected QT interval (QTc), is recommended (LOE: I, GOR: A). QTc should be calculated by either of the two most standardized methods—Bazett’s or Fridericia’s—and the comparative measurements during treatment should all be done using the same method. 2.3. In patients scheduled to undergo cancer therapy associated with heart failure (HF) or left ventricular dysfunction (LVD), baseline evaluation of left ventricular ejection fraction (LVEF), with strain imaging when possible, and diastolic function according to accepted comprehensive imaging practice is recommended (LOE: I, GOR: A).
3. Before cancer treatment: Primary prevention therapy	3.1. In patients with a normal LVEF scheduled to undergo cancer therapy with known cardiotoxic agents and risk factors for cardiac toxicity, prophylactic use of angiotensin converting enzyme inhibitors (ACEIs) or alternatively, angiotensin receptor blocker (ARB), and/or selected beta-blockers (BB) may be considered to reduce the risk of cardiotoxicity (LOE: II, GOR: B). Dexrazoxane has been validated as a cardio-protectant in selected populations who are receiving anthracycline-based chemotherapy (LOE: II, GOR: C). In patients with pre-existing cardiomyopathy who require anthracycline-based ChT, concomitant administration of dexrazoxane from the beginning of anthracycline therapy can be considered regardless of the type of cancer (LOE: III, GOR: C). 3.2. Patients with evidence of hyperlipidemia may benefit from treatment during active cancer therapy, especially cardiotoxic chemotherapy (LOE: II, GOR: C).
4. During cancer treatment: Cardiac safety surveillance	4.1. The following general principles are recommended for medical imaging in patients with cancer at risk for cardiac complications particularly for the periodic assessment of LV systolic function: Highly reproducible, quantitative volumetric, non-irradiating imaging with quality control is recommended (quantitative 2-dimensional [2D] and 3-dimensional [3D] echocardiography, and cardiac MRI) (LOE: I, GOR: A). For each patient, the same imaging modality at the same facility is highly recommended for serial testing (LOE: I, GOR: A). LV global longitudinal strain (GLS) imaging may be considered, when available, for baseline and serial LV systolic function monitoring (LOE: III, GOR: C). 4.2. Asymptomatic patients receiving anthracycline-based chemotherapy with no cardiac biomarker or imaging abnormalities should undergo surveillance for risk stratification and the early detection of cardiac toxicity: Periodic (every 3 to 6 weeks or prior to each cycle) measurement of TnI or TnT and BNP or NT-proBNP using the same institutional laboratory with an acceptable 99% upper limit of normal reference range being the threshold for abnormal (LOE: III, GOR: C) Reassessment of LVEF and GLS (when possible) following the general imaging principles is recommended after a cumulative dose of 250 mg/m ² of doxorubicin or its equivalent anthracycline, after approximately each additional 100 mg/m ² (or ≈200 mg/m ² of epirubicin) beyond 250 mg/m ² , and at the end of therapy even if the cumulative dose is less than 400 mg/m ² (LOE: I, GOR: A). 4.3. Aligned to the current recommendations by the FDA for asymptomatic non-metastatic patients undergoing adjuvant trastuzumab treatment, routine surveillance consisting of cardiac imaging every 3 months should be considered for the early detection of cardiac toxicity. However, the effectiveness of this strategy in patients at low CV risk with no evidence of early LV dysfunction has not been demonstrated (LOE: II, GOR: B). 4.4. Cardiac biomarker assessment may be considered as a valuable tool for cardiac safety surveillance in patients receiving adjuvant anti-HER2-based treatment (LOE: III, GOR: C). 4.5. Asymptomatic patients receiving anti-HER2-based treatment (trastuzumab, pertuzumab, T-DM1) for metastatic disease should have general surveillance for cardiac toxicity that may consist of periodic physical examination, cardiac biomarkers, and/or cardiac imaging (LOE: I, GOR: B). 4.6. In patients receiving cancer therapeutics associated with risk of systemic hypertension, especially anti-VEGF based therapy, establishment of a baseline BP measurement and serial BP monitoring is recommended along with surveillance for the early detection of CV toxicity that may consist of periodic cardiac examination, cardiac biomarkers, and/or cardiac imaging (LOE: I, GOR: A).
5. During cancer treatment: Asymptomatic, new laboratory abnormalities (or preclinical toxicity)	5.1. In asymptomatic patients receiving treatment with anthracyclines, an LVEF decrease of ≥10% from baseline to below 50%, or decrease in LVEF to ≥40% but <50%, the following evaluations are recommended (LOE: III, GOR: A): Cardiology consultation (preferably a cardio-oncology specialist) Consider initiation of cardio-protective treatment (ACEI or ARB ± BB, and perhaps a statin), if not already prescribed Consider measuring cardiac biomarkers (TnI or TnT and BNP or NT-proBNP) and perform a cardiac-focused physical exam after each dose of anthracycline Repeat LVEF ± GLS measurement after every other dose of anthracycline-based chemotherapy If further anthracycline therapy is planned, the benefit-risk assessment of continued anthracycline-based therapy as well as options of non-anthracycline regimens should be discussed, and there should be consideration for the use of dexrazoxane and/or liposomal doxorubicin 5.2. In asymptomatic patients receiving treatment with trastuzumab, an LVEF decrease of ≥10% from baseline to below 50%, or a decrease in LVEF to ≥40% but <50%, the following evaluations are recommended (LOE: III, GOR: A): Cardiology consultation (preferably a cardio-oncology specialist) Consider initiation of cardio-protective treatment (ACEI or ARB ± BB), if not already prescribed Consider measuring cardiac biomarkers (TnI or TnT and BNP or NT-proBNP) at a suggested interval of every 4 to 6 weeks and perform a periodic cardiac-focused physical examination for ongoing monitoring of cardiac toxicity. Repeat LVEF ± GLS measurement within 3 to 6 weeks after holding trastuzumab, and if LVEF ± GLS has normalized, trastuzumab therapy can be resumed 5.3. In asymptomatic patients receiving treatment with any cardiotoxic cancer therapy with normal LVEF but decrease in average GLS from baseline assessment (≥12% relative decrease or ≥5% absolute decrease), the following evaluation and treatment should be considered (LOE: III, GOR: B): Consider initiation of cardio-protective treatment (ACEI or ARB ± BB), if not already prescribed Repeat LVEF ± GLS measurement every 3 months, or sooner, if cardiac symptoms develop Life-saving cancer treatment should not be altered solely based on changes in LV strain 5.4. In asymptomatic patients undergoing treatment with cardiotoxic anticancer therapy and an elevation in cardiac troponin, the following measures should be considered (LOE: III, GOR: C): Cardiology consultation, preferably a cardio-oncology specialist. Consider LVEF and GLS assessment with echocardiography. Appropriate evaluation to exclude ischemic heart disease as a comorbidity. Consider initiation of cardioprotective treatments (ACEIs, ARBs, and/or BBs), if not already prescribed. Consider initiation of dexrazoxane in patients undergoing anthracycline-based ChT. It is possible that anticancer therapy may be continued without interruption if only mild elevations in cardiac biomarkers occur without significant LVD.
6. During cancer treatment: Clinical cardiac dysfunction	6.1. In patients with an abnormal LVEF <50% but ≥40%, medical therapy with an ACEI (or ARB) and/or BB is recommended prior to starting potential cardiotoxic treatment (LOE: I, GOR: A). 6.2. For those with an LVEF <40%, anthracycline therapy, in particular, is not recommended unless there is no other effective alternative cancer treatment option (LOE: IV, GOR: A). 6.3. For a patient receiving treatment with any cardiotoxic agent presenting with potentially cardiac-related but unexplained signs and symptoms such as (but not limited to) sinus tachycardia, rapid weight gain, dyspnea, peripheral edema, or ascites, it is recommended to obtain a cardio-oncology consultation, reassess LVEF ± GLS, and potentially measure cardiac biomarkers (LOE: III, GOR: A). 6.4. For a patient receiving treatment with trastuzumab (or any HER2-targeted molecular therapy) with signs and symptoms of heart failure, or an asymptomatic patient with an LVEF <40%, the same assessments as those for an LVEF ≥40% are recommended. In addition, trastuzumab (or any HER2-targeted molecular therapy) should be held until the cardiac status has stabilized and a discussion regarding the risk/benefits of continuation should be held with the multidisciplinary team and the patient (LOE: I, GOR: A). 6.5. For a patient in whom trastuzumab (or any HER2-targeted molecular therapy) has been interrupted, whose LVEF has increased to ≥40% and/or whose signs and symptoms of heart failure have resolved, resumption of trastuzumab (or any HER2-targeted molecular therapy) should be considered, along with the following recommendations (LOE: III, GOR: B): Continued medical therapy for heart failure and ongoing cardiology care Periodic cardiac biomarker (BNP or NT-proBNP) assessment Periodic LVEF assessments during ongoing treatment 6.6. For a patient in whom trastuzumab (or any HER2-targeted molecular therapy) has been interrupted, whose signs and symptoms of heart failure do not resolve, whose cardiac biomarker does not normalize, and/or LVEF remains <40%, resumption of trastuzumab may be considered if no alternative therapeutic options exist. The risk-benefit assessment of prognosis from cancer versus heart failure should be discussed with the multidisciplinary team and the patient (LOE: IV, GOR: C). 6.7. For a patient receiving treatment with sunitinib (or any other anti-VEGF-based therapy) with signs and symptoms of heart failure, assessment of BP control is recommended and measurement of LVEF and/or cardiac biomarkers should be considered. In addition, sunitinib (or any other anti-VEGF-based therapies) should be interrupted until the appropriateness of reinstituting this therapy has been fully assessed (LOE: III, GOR: A).
7. After cancer treatment	7.1. For asymptomatic patients who have been treated with cardiotoxic agents and have normal cardiac function, periodic screening for the development of new asymptomatic LV dysfunction with cardiac biomarkers and potentially cardiac imaging should be considered at 1 and 2 years posttreatment, and consideration for reassessment periodically thereafter (LOE: III, GOR: B). 7.2. For patients who developed asymptomatic LV dysfunction or heart failure due to trastuzumab (or any other HER2-targeted molecular therapy), anthracycline, or other cancer therapy, CV care including medical treatment with ACEI (or ARB) and/or BB, and regular CV evaluation (e.g., annually, if asymptomatic) should be continued indefinitely, regardless of improvement in LVEF or symptoms. Any decision to withdraw guideline-based medical therapy should only be done after a period of stability, no active cardiac risk factors, and no further active cancer therapy (LOE: III, GOR: B). 7.3. For patients with a history of mediastinal or chest radiation, evaluation for coronary artery disease and myocardial ischemia as well as valvular heart disease is recommended, even if asymptomatic, starting at 5 years posttreatment and then at least every 3–5 years thereafter (LOE: I, GOR: A).
8. Immune checkpoint inhibitor-associated CV toxicity	8.1. For patients who develop new CV symptoms or are incidentally noted to have any arrhythmia, conduction abnormality on ECG, or left ventricular systolic dysfunction (LVSD) on echocardiogram, while undergoing (or after recent completion) of ICI therapy, further appropriate workup (ECG, troponin, BNP or NT-pro-BNP, C-reactive protein, viral titer, echocardiogram with GLS, cardiac MRI) for ICI-associated CV toxicity, particularly myocarditis and other common differential diagnoses should be carried out promptly (LOE: IV, GOR: C). 8.2. Endomyocardial biopsy for diagnosis should be considered if the diagnosis is highly suspected with an otherwise negative workup (LOE:IV, GOR:C). 8.3. With either suspicion or confirmation of ICI-associated myocarditis, further therapy with ICIs should be withheld and high-dose corticosteroids (methylprednisolone 1000 mg/day followed by oral prednisone 1 mg/kg/day) should be initiated promptly. Corticosteroids should be continued until resolution of symptoms and normalization of troponin, LV systolic function, and conduction abnormalities (LOE: IV, GOR: C). 8.4. For steroid-refractory or high-grade myocarditis with hemodynamic instability, other immunosuppressive therapies such as anti-thymocyte globulin, infliximab (except in patients with HF), mycophenolate mofetil, or abatacept should be considered (LOE: IV, GOR: C). 8.5. For patients with cardiomyopathy and/or HF, appropriate guideline-directed medical therapy and hemodynamic support should be provided as indicated (LOE: IV, GOR: C). 8.6. For patients with atrial or ventricular tachyarrhythmia or heart block, appropriate medical and supportive care should be provided as indicated (LOE: IV, GOR: C). 8.7. ICI therapy should be permanently discontinued with any clinical myocarditis. The decision regarding restarting ICI therapy in the absence of alternative available antineoplastic therapy needs to be individualized with multidisciplinary discussion considering the cancer status, response to prior therapy, severity of cardiotoxicity, regression of toxicity with immunosuppressive therapy, and patient preference after weighing the risks and benefits. If ICI therapy needs to be restarted, monotherapy with an anti-programmed cell death protein 1 (anti-PD-1) agent might be considered with very close surveillance for cardiotoxicity development (LOE: V, GOR: C).
Level of evidence	I. Evidence from at least one large randomized, controlled trial of good methodological quality (low potential for bias) or meta-analyses of well-conducted randomized trials without heterogeneity II. Small randomized trials or large randomized trials with a suspicion of bias (lower methodological quality) or meta-analyses of such trials or of trials with demonstrated heterogeneity III. Prospective cohort studies IV. Retrospective cohort studies or case-control studies V. Studies without control groups, case reports, expert opinions
Grading of recommendation	A. Strong evidence for efficacy with a substantial clinical benefit, strongly recommended B. Strong or moderate evidence for efficacy but with a limited clinical benefit, generally recommended C. Insufficient evidence for efficacy or benefit does not outweigh the risk or the disadvantages (adverse events, costs, etc.), optional D. Moderate evidence against efficacy or for adverse outcome, generally not recommended E. Strong evidence against efficacy or for adverse outcome, never recommended

BP, Blood pressure; CV, cardiovascular; CVD, cardiovascular diseases; ESMO, European Society of Medicine Oncology; ICI , immune checkpoint inhibitor; MRI, magnetic resonance imaging; VEGF , vascular endothelial growth factor.

Cardiomyopathy/Heart Failure Management

Cardiotoxicity is commonly used as an umbrella term for any cardiac abnormality encountered with cancer therapy. The first step is therefore to define the abnormality, its causes, and implications. Of the advocated cardiac surveillance parameters, left ventricular ejection fraction (LVEF) is most commonly reported and reacted to. That being said, various consensus documents have forwarded different definitions of cardiotoxicity, and the consensus definition that emerges is a drop of greater than 10% to below the lower limit of normal, which is set at 53% in the ASE/EACI consensus and at 50% in the ESMO consensus. ^, The cutoff to stop cancer therapy is not universally defined but most would agree with an LVEF of 40% as originally outlined for trastuzumab therapy for cessation of therapy and as outlined in the most recent ESMO document. Cancer therapy of any type is to be discontinued in any patient who develops HF. These patients as well as those with an EF less than 50% should receive neurohormonal therapy in accordance with the American Heart Association (AHA)/American College of Cardiology (ACC) HF guidelines ( Chapter 50 ). For global longitudinal strain (GLS), a 15% relative change (confirmed within 2 to 3 weeks upon repeat assessment) is considered to represent subclinical left ventricular dysfunction and is predictive of a more evident future decline in LVEF. At present, however, there is no clear guidance how to react to such changes. The same holds true for cTn elevations, though it has been used as a trigger to start ACE inhibitor therapy. For both parameters, the main merit is in the high negative predictive value.

As outlined above, it is important not to default to the assumption that a decline in cardiac function is always due to the cancer therapy, and even when it is, that is always due to a direct (toxic) effect on the cardiomyocytes. Some cancer therapeutics affect the vasculature more so than the myocardium and a decline in cardiac function is seen because of a reduction in blood supply. This would be even more so in the case in patients with CAD and other CVD conditions. The pre-therapy evaluation therefore serves a very important role as does an evaluation for any additional contributing factor during therapy should complications arise. Very important in view of the increasing use and the potential fatal implications is the recognition of ICI myocarditis ( Fig. 57.4 ). For further discussion on cardiomyopathy management see the supplemental text online.

$FIGURE 57.4, Outline of the approach to immune checkpoint inhibitor (ICI) myocarditis. Some patients on ICI therapy may undergo routine, serial (e.g., every 4 weeks) testing with biomarkers (cardiac troponin and natriuretic peptides) and electrocardiograms (ECG), while others present with symptoms that raise concerns for myocarditis. The work-up includes cardiac imaging studies, coronary angiography, and endomyocardial biopsy as prompted clinically. ICI therapy is to be stopped and steroids are to be started already at this stage. Once a diagnosis of myocarditis is substantiated, steroids are continued with additional immunosuppressive therapies as needed. Depending on the grade/severity of myocarditis, ICI is not to be resumed. CK, creatine kinase; BNP, brain natriuretic peptide; ECG, electrocardiogram; LVEF, left ventricular ejection fraction; MRI, magnetic resonance imaging; PET, positron emission tomography; TTE, transthoracic echocardiogram; RWMA, regional wall motion abnormalities.$

Vascular Disease Management

Management of VTE in cancer patients is challenging because of their predisposition to both thrombosis and bleeding. Recurrence of VTE despite anticoagulation (so-called anticoagulation failure) is seen in 15% of patients on warfarin (rate of 2.5% per month). LMWH has superior efficacy in this regard at similar major bleeding rates than warfarin. Compared with LMWH, DOACs have similar (edoxaban) or improved (rivaroxaban, apixaban) efficacy rates but higher bleeding rates, especially gastrointestinal (GI) bleeding rates. Patients with mucosal tumors (GI/GU malignancy) should receive anticoagulation other than with DOACs. Treatment should continue for as long as the cancer disease process is deemed active, and at a minimum for 3 to 6 months.

As outlined above, cancer patients are also at risk of ATEs, and presentations range from unstable angina to MI with and without arrhythmias (polymorphic ventricular tachycardia [VT] or heart block) in the coronary circulation, from transient ischemic attack to stroke in the carotid/cerebral circulation, and bowel ischemia, acute renal failure, and critical limb ischemia in the peripheral circulation. Treatment is in agreement with current practice guidelines and is outlined in Chapter 43, Chapter 45 . Antiplatelet therapy is a key element and based on current ACC/AHA guidelines, dual antiplatelet therapy (DAPT) should be continued for 1 year in patients with ACS, thereafter guided by risk calculators such as the DAPT score (see also Chapter 37, Chapter 40 ). These, however, do not take malignancy into consideration. Similar to VTE recommendations, one might argue for the continuation of DAPT as long as active cancer is present; however, there are no data for such a recommendation yet. Moreover, all of these interventions need to be balanced with the bleeding risk. In this context thrombocytopenia is an important factor to consider and the Society for Cardiovascular Angiography and Interventions (SCAI) recommendations for platelet cutoffs are as following: for surgical interventions platelet counts greater than 50K are recommended, for percutaneous coronary intervention (PCI) with DAPT platelet counts greater than 30K, and for angiography platelet counts greater than 10K.

While acute coronary vasospasm, especially if profound and prolonged, can lead to MI, VT/ventricular fibrillation to the point of sudden cardiac death (SCD), and cardiac dysfunction, even Takotsubo’s, HF, and cardiogenic shock, the typical presentation is angina with concomitant ST-segment elevation on ECG, resolving promptly with vasodilator therapy. In case of 5-FU, the presentation can be so typical that treatment with vasodilator therapy is both diagnostic and therapeutic. For patients experiencing acute vasospasm, vasodilators such as nitrates and calcium channel blockers (CCBs) are mainstay therapy and have been used even in combination. For further discussion on management of acute vasospasm as well as accelerated atherosclerosis see the supplemental text online.

Arrhythmia Management

QTc prolongation noted on surveillance ECGs should prompt the adjustment of therapy. For most drugs, therapy should be held if the QTc interval exceeds 500 msec and resumed at a reduced dose upon resolution of QTc prolongation. With nilotinib, any QTc greater than 480 msec requires cessation of therapy until the QTc is 450 to 480 msec (then resume therapy at half dose) or less than 450 msec (then resume therapy at full dose). Any grade 4 (that is, life-threatening) QTc event also precludes any further cancer therapy. Ventricular arrhythmias should be managed as usual according to clinical guidelines. Important to address in cancer patients on multiple other medications are drug-drug interactions and electrolyte abnormalities (goal value for serum K ⁺ levels ≥4 mEq/L and for calcium and magnesium within normal limits).

The principles and goals of the management of AF in patients with cancer are generally the same as those in the general population, albeit with some important nuances. The first is a more lenient heart rate goal (<115 beats/min [bpm]) with the use of beta-blockers, CCBs, and digoxin. The second is the potential for drug-drug interactions, especially with antiarrhythmic drugs, which are indicated if patients remain symptomatic. An illustrating example is ibrutinib as outlined in the extended online content.

Anticoagulation in patients with cancer can be problematic in general and especially in patients receiving ibrutinib because of a predisposition to bleeding. Ibrutinib has a unique antiplatelet effect, inhibiting mainly von Willebrand factor (vWF) and collagen-mediated platelet activation (in addition to fibrinogen-activated platelet activation). Importantly, these activation pathways are distinct from those inhibited by aspirin (cyclooxygenase) and thienopyridines adenosine diphosphate ((ADP) receptor), and combination therapy would lead to a profoundly additive effect and bleeding risk; therefore, this strategy is not recommended. Anticoagulation strategies in cancer patients are outlined above. For further discussion on management of arrhythmias see the supplemental text online.

Approach to the Cancer Patient at Risk of or with Cardiovascular Diseases After Cancer Therapy

Patients who have completed their cancer therapy and are cured of their disease (survivors) remain at risk of secondary malignancies as well as long-term consequences and complications of their malignancy and its treatment. These patients are referred to see a cardiologist to discuss long-term risk and preventive strategies. Often though, cardiologists may encounter these patients presenting with CVD, which can be due to (a) the continuum of vascular disease that was present even before the cancer treatment, and/or (b) the new development of vascular disease during or after completion of cancer therapy. Whereas the first scenario requires follow-up and treatment in keeping with published guidelines, the second scenario has to take into account the uniqueness of the cancer therapy the patient has received. Some cancer therapeutics affect the CV system only for the time of therapy, and especially if any impact is ruled out at the time, any newly developing CVD years later is very difficult to causally link to it. The situation is different with cancer therapies that have a prolonged effect and late onset. Cultivating an understanding of the most likely clinical course and potential contributing mechanisms is again the most recommendable approach.

Cardiomyopathy/Heart Failure in Cancer Survivorship

The profound impact cancer therapies can have on the CV system has been very well illustrated in cardiopulmonary exercise studies outlining a drop in peak VO ₂ ( eFig. 57.1 ). A sharp decline in exercise capacity is seen after cancer therapy, which, however, may not become evident at the time. It may, and likely will with additional risk factors, progress to the symptomatic stage. This matches conceptually the progression through the AHA HF stages. Patients after exposure to cardiotoxic therapy are considered to be in Stage A HF just like patients with hypertension, diabetes, and other well-known risk predisposition. How to best follow these patients and when to act and in which format is not well defined. Serial echocardiographic studies over the first 3 years after cancer therapy indicate that the main negative deflection in LVEF is occurring in the first year after start of cancer therapy. This provides the rationale for current American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) follow-up recommendations (see below). However, several studies do outline a cumulative increase in HF presentations over time and not only in patients after anthracycline-based therapy, but also in patients after trastuzumab treatment and especially after the combination of these agents. ^, Reportedly, breast cancer patients who underwent chemotherapy also have an increased risk of late (10+ years) CV mortality. The sequence and causal link of reduction of cardiac function, HF, and mortality in these patients is yet to be proven though, as is the mantra of early detection and intervention. Following radiation therapy, an increase in HF rates is seen after 15 years in breast cancer patients and an exponential increase in CV events follow the same timeline in lymphoma patients after chest radiation. The effects of anthracycline exposure and radiation therapy are additive. While anthracycline therapy in adults leads to a dilative cardiomyopathy and HF with reduced LVEF, radiation therapy classically leads to a restrictive cardiomyopathy and HF with preserved LVEF. As HF can be the final common pathway of the various elements in the spectrum of radiation-induced heart disease, all contributing factors need to be evaluated, including ischemic and structural heart disease. Otherwise, treatment recommendations follow the ACC/AHA HF guidelines for the various stages of HF. Exercise is to be encouraged and cardio-oncology rehabilitation programs have emerged. For further discussion on cardiomyopathy/HF in cancer survivorship see the supplemental text online.

EFIGURE 57.1, Trajectory of the decline in cardiovascular reserve capacity (CVRC) across the cancer continuum. Cancer patients exposed to cardiotoxic therapies are at risk of progressing through the American Heart Association stages of heart failure. A decline in CVRC is typically seen during cancer therapy with various response patterns thereafter. The goal is to prevent and to restore, as much as possible, any decline in cardiac function.

Vascular Disease in Cancer Survivorship

Cancer patients have a sixfold higher risk of VTE recurrence with an annual rate as high as 30% in the absence of anticoagulation and as high as 20% even within the initial 6 months on anticoagulation therapy. The rate of VTE recurrence differs significantly by cancer type, stage of disease, and progression over time; specific risk factors include brain, lung, pancreatic, or ovarian cancer; myeloproliferative or myelodysplastic disorders; stage IV cancer; cancer stage progression; or leg paresis. The original and modified Ottawa prediction scores were developed to risk stratify for recurrent VTE; among the variables included in the score, female gender and lung cancer increase the risk, whereas breast cancer and stage I (/II) decrease the risk. If outlined risk factors are present, it is likely best to continue anticoagulation (premature discontinuation of anticoagulation should be avoided). Importantly, the risk for VTE remains increased in cancer survivors, especially in childhood cancer survivors who face a 25-fold higher risk than their non-diseased siblings. ^,

In terms of VTE, most cancer therapies do not pose a long-term risk though exceptions need to be recognized. The first is cisplatin, and its circulating levels can remain detectable for decades after completion of cancer therapy. The second is Bcr-Abl TKIs, especially nilotinib and ponatinib, though ischemic events may not relate to thrombosis (alone); the same holds true for radiation therapy. Proactive screening for thrombosis is usually not done; the evaluation is driven by signs and symptoms. In these patients it remains important to consider embolic thrombotic events (VTE with patent foramen oval, marantic endocarditis, AF, atrial or ventricular thrombus) as well as plaque rupture or erosion with subsequent in situ thrombosis. Treatment is directed toward the underlying etiology and per guidelines with options including anticoagulation, fibrinolysis, antiplatelet therapy, and revascularization. ^, Preventive efforts are mainly secondary prevention efforts and are directed toward improving endothelial health and reducing the risk of thrombus formation. For the long-term (>1 year past event) use of DAPT, the presumed anti-ischemic benefit must be weighed against the bleeding risk. Calculators to estimate these risks are available but need to be validated in cancer patients and the long-term dynamics of thrombotic risk in these patients remain to be defined. ^,

For many years after completion of therapy, cancer patients can experience an altered vasoreactivity profile, which can present as typical and atypical angina, microvascular angina, cardiac syndrome X, and Raynaud’s. CCBs are usually first-line therapy for patients with Raynaud’s, especially slow-release/long-acting dihydropyridine CCB such as nifedipine XL. They may also be more effective than nitrates in cases of microcirculatory involvement (microvascular angina).

Accelerated atherosclerosis is the leading entity in terms of vascular risk after completion of cancer therapy. The risk is particularly high in patients who received Bcr-Abl inhibitors or radiation therapy, and also after allogenic bone marrow transplantation. These patients may benefit from preemptive screening of vascular territories most likely to be involved, including ankle-brachial index (ABI), carotid ultrasound and noninvasive coronary imaging, and stress tests. Following chest radiation therapy, consensus guidelines recommend a cardiac stress test every 5 years in patients with defined high-risk features. As the increase in risk with the combination of radiation therapy and CV risk factors is profound, regular screening for these is recommended. For patients who present with accelerated atherosclerosis (progressive arterial occlusive disease), treatment is in keeping with societal guidelines. For further discussion on vascular disease in cancer survivorship see the supplemental text online.

Arrhythmias in Cancer Survivorship

Arrhythmias in cancer survivors are most commonly expected after radiation therapy to the chest and therapies that exerted a lasting negative effect on cardiac function. This includes patients who sustained a MI as a consequence of cancer therapy with subsequent scar formation. Patients after anthracycline therapy may have such poor heart function that they are at risk of malignant arrhythmias and SCD. Indeed, current literature is supportive of the fact that among patients with a LVEF less than 35% and meeting qualifications for an ICD/cardiac resynchronization therapy-defibrillator (CRT-D) the risk of VT and ventricular fibrillation and the benefit from device therapy is the same for anthracycline and dilated/ischemic cardiomyopathy. Device therapy should therefore not be withheld for cancer survivors. AF can be seen in those with cardiomyopathy or valvular heart disease, especially after radiation therapy. Management follows standard guidelines. Heart block can be seen after radiation therapy. Sinus tachycardia is by far the most common rhythm abnormality in cancer patients, even as a reflection of autonomic dysfunction, after radiation as well as after anthracycline therapy.

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