Cancer and the cardiovascular system share numerous risk factors.17 No prospective scoring systems are currently available for jointly evaluating cardiovascular risk (CVR) and cardiotoxicity risk, and traditional scales underestimate the risk associated with cancer treatment.3 Despite this limitation, CVR should be stratified using SCORE tables before anticancer therapy initiation (Figure 1),18 and physicians should evaluate the presence of factors determined in retrospective studies and registries to increase the risk of cardiovascular events during anticancer therapy (Table 1).9–12,14,19,20

Figure 1.

Stratification of cardiovascular risk.18 CKD, chronic kidney disease; CVD, cardiovascular disease; CVR, cardiovascular risk; CVRF, cardiovascular risk factor; DL, dyslipidemia; DM, diabetes mellitus; GF, glomerular filtration; HT, hypertension. aA tool for SCORE calculation is available in the multimedia section of the Spanish Society of Cardiology website. bIndependently of the calculated SCORE (%), the presence of these factors is associated with a high or very high CVR.

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The following strategy should be applied to all patients, independently of the planned treatment:

• •

  Promotion of a heart-healthy lifestyle with a regular exercise program.21

• •

  Identification and strict control of CVR factors (CVRFs) before, during, and after treatment. The therapeutic targets are summarized in Table 2 and are similar to those in the general population.18,22

  Table 2.

  Therapuetic Targets for Cardiovascular Risk Factors18,22

  CVRFs	Targets
  LDL-C*	Very high risk, < 70 mg/dL Moderate/high risk, < 100 mg/dL
  Blood pressure	< 140/90 mmHg < 140/85mmHg (diabetes mellitus or chronic kidney disease)
  HbA1c	< 7% (> 75 y, 7.5%-8%)
  Diet	Heart-healthy
  Smoking	No
  Exercise	≥ 150min per week of moderate exercise

  CVRFs, cardiovascular risk factors; HbA1c, glycated hemoglobin; LDL-C, low-density lipoprotein-cholesterol.

  *

  Patients who are going to receive or have received cardiotoxic anticancer treatments should be considered to have high cardiovascular risk, independently of the SCORE.

The following strategy is recommended during the administration of potentially cardiotoxic treatments:

• •

  Reduction of the direct cardiotoxic effect via the use of less cardiotoxic therapeutic regimens (liposomal formulations).9,23

• •

  Use of cardioprotective agents in primary prevention.

  • –

    Dexrazoxane: reduces the risk of CTRCD due to anthracyclines but its use is controversial and atypical in Europe.9

  • –

    Beta-blockers (carvedilol and nebivolol): prevent a LVEF reduction and decrease the incidence of heart failure (HF) during trastuzumab and/or anthracycline therapy.24,25

  • –

    Angiotensin-converting enzyme (ACE) inhibitors: enalapril prevents LVEF deterioration in patients with troponin elevation during anthracycline therapy.26

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    Combination therapies: the OVERCOME trial found reduced ventricular dysfunction (VD) and a lower incidence of death or HF in hematology patients under treatment with carvedilol and enalapril vs placebo.27 In patients with breast cancer, the PRADA study showed a cardioprotective effect of candesartan (but not candesartan and metoprolol combination) vs placebo.28

  • –

    Statins: high-potency statins have been shown in vitro and in retrospective studies to reduce cellular damage and HF risk in patients under treatment with anthracyclines.9,23,24

  • –

    Initial data23 support the use of aldosterone inhibitors in HF prevention.

Systematic use of cardioprotective agents is not currently recommended for all cancer patients but they should be used in patients with previous heart disease and/or arterial hypertension (HT). They can be considered in primary prevention for patients with high or very high CVR or those who have previously received cardiotoxic drugs and require new anticancer treatment.9,18

In addition to optimizing CVR and considering primary prevention strategies, cardio-onco-hematology teams should coordinate the monitoring of anticancer treatments for the identification and early treatment of possible cardiovascular complications (Table 3).7,9,14 The following patients should be referred to a cardiologist to evaluate the need for cardiac treatment and/or intensive monitoring9,14: those with poor control of CVRFs, significant alterations in imaging or biomarker studies, and/or heart disease symptoms.

Biomarkers are tools for the early detection of myocardial damage.9,14,29,30 Troponin levels should be determined at baseline and before each cycle.31 An early (< 72 hours) troponin I (TnI) elevation (> 0.08 ng/dL) is detected in one-third of patients treated with anthracyclines.32 Persistent TnI elevation during cancer treatment identifies patients with worse cardiovascular prognosis who could benefit from ACE inhibitors to reduce CVD risk, avoiding the need for anticancer therapy withdrawal or modification.14,32 Less well-defined predictors of VD are the use of N-terminal pro-B type natriuretic peptide (NT-proBNP), a diagnostic marker of HF, and other biomarkers and/or other anticancer agents.31

Echocardiography enables a general cardiac evaluation and is the technique of choice for serial measurement of LVEF. Two-dimensional (2D) LVEF shows poor sensitivity for the detection of minor changes in cardiac function because its variability is close to the diagnostic range of CTRCD (8%-11%).33 Contrast agent use and a systematic review of previous studies13 have improved the diagnostic accuracy. When available and used in experienced centers, 3-dimensional LVEF shows less variability (5.8%)34 and is the recommended echocardiographic technique for treatment monitoring (Table 4).9,14,35,36 Due to reduced availability, the use of cardiac magnetic resonance imaging, the reference standard for LVEF quantification, is limited to patients with unclear echocardiographic results.9,14,37 Isotopic ventriculography should not currently be considered for monitoring onco-hematologic treatments due to the risk associated wit ionizing radiation.9

Once CTRCD has developed, initiation of HF treatment based on 2D LVEF alone does not guarantee functional recovery.38 New techniques, such as 2D speckle tracking, can identify myocardial damage at an even earlier stage by studying myocardial deformation (“strain”).39 At baseline, global longitudinal strain (GLS) improves the stratification of CTRCD risk vs 2D LVEF.40 During anticancer therapy, GLS reveals myocardial damage at an earlier stage and with less variability than LVEF (intraobserver, < 4%; interobserver, < 6%).41–45 Evaluation is recommended of relative changes in GLS, instead of absolute values, as well as the use of the same equipment and quantification software. Global longitudinal strain reductions > 15% from baseline indicate structural cardiac damage (stage B HF).9,14,46 Combination use of GLS and TnI improves their negative predictive value for VD and, thus, HF risk stratification.9,14

Heart failure diagnosis is based on the presence of its typical symptoms and signs and echocardiographic alterations or an elevation in natriuretic peptides.16,47 If HF is present, physicians should adhere to the conventional treatment algorithms and rule out ischemic heart disease.16,47

Beta-blocker and ACE inhibitors treatment of patients with reduced LVEF, whether symptomatic or asymptomatic, is required to avoid clinical HF and ventricular remodeling.11,16 Elevated levels of troponins and/or a GLS decrease > 15% with normal LVEF identify patients with asymptomatic structural damage (stage B HF) and at greater risk of progression to HF.14,46 Initial studies support the use of ACE inhibitors, with or without beta-blockers, to avoid withdrawal of potentially curative anticancer therapies.15,32,38,48

The indication for onco-hematology treatment withdrawal/delay should be individualized by weighing HF risk against that of cancer relapse/progression (Table 1 and Table 2 of the supplementary material and Figure 4).9,14,29,49,50

Figure 4.

Treatment and monitoring of patients receiving cardiotoxic agents and with a LVEF < 53%.9,14,16,29,49,50 ACE, angiotensin-converting enzyme; BBs, beta-blockers; HF, heart failure; HT, hypertension; LVEF, left ventricular ejection fraction. *See Table 4 of the supplementary material.

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Heart failure treatment duration after LVEF normalization is controversial. Early withdrawal is not recommended. However, it can be considered, under strict surveillance, for asymptomatic patients without CVRFs and with normal parameters and stable ventricular function for more than 1 year (LVEF, GLS, TnI, and NT-proBNP).51 For patients with VD despite optimal treatment, the guidelines for HF should be followed regarding device implantation or heart transplant when permitted by the patient's vital prognosis.16,47

HT is the most common comorbidity in cancer patients.8 Onco-hematology therapies cause HT via different mechanisms but the most frequently involved treatments are drugs that inhibit angiogenesis, interact with vascular endothelial growth factor (anti-VEGF agents), and decrease nitric oxide production.52 The incidence and severity of the resultant HT depend on the tumor, the drug, and the presence of other CVRFs (Table 1, Table 2, and Table 4 of the supplementary material).53,54 Although HT caused by anti-VEGF therapy can predict a good tumor response, its control does not reduce therapeutic effectiveness55 but does avoid cardiovascular complications and treatment interruption.50 An initial assessment and close monitoring of blood pressure is recommended during the therapy by following the pharmacological and nutritional recommendations for the general population. The target blood pressure is < 140/90mmHg for patients with uncomplicated HT and < 140/85mmHg for diabetic patients and those with renal failure.56 Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and beta-blockers are the first-line drugs due to their ability to protect against HF development. If control is poor, amlodipine and aldosterone antagonists should be added. Thiazides should be used with caution due to the risk of hyperkalemia and QTc prolongation. Negative inotropes (diltiazem and verapamil) are discouraged due to the risk of HF and drug interactions (cytochrome P450 inhibitors increase sorafenib concentration) (Figure 5).57

Figure 5.

Protocol for initiation, monitoring, and treatment of blood pressure in patients with indication for anti-VEGF therapy.9,46,57 ACE, angiotensin-converting enzyme; anti-VEGF, vascular endothelial growth factor inhibitor; ARBs, angiotensin II receptor blockers; BB, beta-blockers; BP, blood pressure; DBP, diastolic blood pressure; ECG, electrocardiography; ECHO, echocardiography; HF, heart failure; HT, hypertension; SBP, systolic blood pressure. *See Table 4 of the supplementary material.

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The therapeutic approach is similar to that of patients without cancer, with consideration of pacemaker implantation for symptomatic bradycardias caused by taxanes and thalidomide, if the treatment has been clearly shown to improve survival.61

Devices

Implanted devices can be affected by radiotherapy. When the generator is located within the therapeutic field, its relocation can be considered to avoid interference. The clinical impact of radiotherapy on the device is directly proportional to the type and dose of energy administered and the degree of patient dependence on the pacing. Protective material, dose modeling, and assessment and follow-up protocols are vital (Figure 7).62 For patients with end-stage disease, antibradycardia pacing should not be modified unless it impairs quality of life but deactivation of antitachycardia therapies should be considered, if the patient agrees.63

Figure 7.

Evaluation and follow-up protocol during RT administration to patients with implanted devices (pacemakers, defibrillators) whose target volume includes at least part of the heart. CTx, chemotherapy; HT, hormone therapy; ICD, implantable cardioverter defibrillator; PMs, pacemakers; RT, radiotherapy.

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Although cancer can cause ischemic heart disease (IHD) via different mechanisms, the most frequent causes are sequelae of anticancer drugs and radiotherapy (Figure 8).9,19

Figure 8.

Manifestations of ischemic heart disease in patients receiving onco-hematology treatment. Anti-VEGFs, vascular endothelial growth factor inhibitors; CVRFs, cardiovascular risk factors; HT, hypertension. *Increased blood viscosity, extrinsic coronary compression.

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Management of Ischemic Complications of Cancer Therapy

There are no recommendations for prophylactic antiplatelet agents. For patients with angina, treatment optimization is recommended, as well as control of precipitating factors such as anemia. Patients with persistent symptoms are candidates for ischemia testing and eventual revascularization to enable therapy tolerance, depending on the risk/benefit ratio. Protocols for the evaluation of chest pain are similar to those for patients without cancer (Figure 9), with individualization of the revascularization strategy and antithrombotic regimen.9

Figure 9.

Treatment algorithm for patients with chest pain in the emergency room. ECG, electrocardiography; LBBB, left bundle branch block. aA 12-lead ECG must be obtained and correctly interpreted within 10minutes, as well as serial troponin measurement. The ECG should be repeated if it is nondiagnostic or the pain disappears or reappears. bIn patients with persistent ST-segment elevation, primary angioplasty should be performed, as long as the patient's vital prognosis permits it and there are no hematological contraindications. cIn patients with non– ST-segment acute coronary syndrome, the risk must be stratified (GRACE scale) and the need for an invasive strategy must be assessed. If dual antiplatelet therapy is required, short courses are preferred and ticagrelor should be avoided in patients with active chemotherapy due to the risk of interactions with cytochrome P450 3A4. dIf the ECG is normal and serial enzymes are negative, ischemia testing should be performed according to the predefined and standardized protocol of the hospital.

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Myocarditis is an uncommon complication of anticancer therapy (Table 1 and Table 2 of the supplementary material)65 that should be confirmed with cardiac magnetic resonance imaging. Its management follows the same criteria as in the general population.66 Immunosuppression can complicate prognosis, particularly in the presence of hemorrhagic myocarditis due to cyclophosphamide or tako-tsubo cardiomyopathy induced by 5-fluorouracil, cytarabine, or rituximab.67 Due to the risk of relapse, it is essential to reevaluate the cancer therapy and maintain cardioprotective efforts, at least until treatment completion.9

Acute pericarditis symptoms are uncommon and their management is similar to that of patients without cancer.68 They are related to chest radiotherapy, anthracyclines, cyclophosphamide, cytarabine, and bleomycin.9,19 Up to 20% of patients can acquire chronic effusive-constrictive forms years after the radiotherapy.19

Radiotherapy can damage the endocardium of valves, causing fibrosis, thickening, and dystrophic calcification.69 The degree of involvement is related to the time elapsed since radiotherapy.19 In autopsies, up to 81% of patients have evidence of valve damage, mainly mitral regurgitation, aortic stenosis, and calcification of the mitral-aortic intervalvular fibrosa.70 The probably of stenosis development increases 13.9 times for every 10 years since the radiotherapy.69 The treatment recommendations are similar to those for the general population, bearing in mind that radiotherapy increases the risk of cardiac surgery and that the type of lesion makes valve repair unlikely.71

Venous thromboembolic disease (VTD), defined as deep vein thrombosis and/or pulmonary embolism, is 4 to 7 times more frequent in onco-hematology patients and has been documented in more than 20% of hospitalized patients with a malignancy.9 Factors associated with VTD are age, genetic predisposition, tumor extent and type (more common in lymphoma, myeloma, and pancreatic, ovarian, lung, stomach, and kidney cancer), and active treatment primarily with TKIs, immunomodulators (thalidomide, lenalidomide, and pomalidomide), 5-fluorouracil, cisplatin, and tamoxifen. These epidemiologic data justify prevention of VTD (Table 5).72,73

Pulmonary hypertension is an uncommon but serious complication that develops months or years after patient exposure to certain antineoplastic agents (TKIs, mainly dasatinib).9 The symptoms generally reverse upon treatment interruption. Cyclophosphamide can produce severe pulmonary hypertension due to pulmonary veno-occlusive disease.74 Diagnosis is based on clinical evaluation, echocardiography, and biomarkers (NT-proBNP). Pulmonary hypertension should be monitored every 3 to 6 months with echocardiography in patients under treatment with TKIs and should be suspected after significant changes in functional class. These patients require a multidisciplinary assessment to determine the best therapeutic strategy.9,75

Peripheral vascular disease after radiotherapy mainly affects the arteries and capillaries and the lesions are distinct from those of classic atherosclerosis (less accumulation of lipids and macrophages, a marked endothelial thickening, destruction of the internal elastic lamina, necrosis of the vasa vasorum, and areas of bleeding within the plaque).9,19 Determination of its incidence is difficult due to the considerable heterogeneity of patient series but up to 70% of patients with head and neck tumors have carotid lesions 2 to 3 years after treatment.76

Administration of certain antineoplastic agents is associated with arterial thromboembolic phenomena (Table 1 and Table 2 of the supplementary material) and early atherosclerosis in the distal part of the extremities (nilotinib or ponatinib).54 The prevention and treatment of atherosclerosis induced by anticancer agents or radiotherapy require close control of CVRFs, particularly in patients with prolonged survival.9,19

About 11% of 40-year-old patients who survived a childhood neoplasm have a severe heart disease, generally HF, or require cardiovascular treatment.3 Systematic screening reduces the cumulative incidence of HF by 18%.77 Coordination of hospital teams with primary care is essential to meet the health care needs of long-term cancer survivors.7

Most of the available information is derived from survivors of childhood cancer. Chow et al.78 developed and validated a HF risk score that classifies survivors into low risk (cumulative incidence of HF at age 40 years of 0.5%), medium risk (2.4%), and high risk (11.7%). The risk depends on the treatment received (cumulative dose of drugs/radiation and combined treatments) and the age at exposure. Follow-up is recommended for survivors who have received an anthracycline dose ≥ 250mg/m2 or ≥ 35Gy of chest radiotherapy or combined treatment with ≥ 100mg/m2 anthracyclines and ≥ 15Gy. Follow-up of low-risk survivors (anthracyclines < 100mg/m2 or < 15Gy) has not shown benefit.79

There is general agreement on the need for monitoring but not on how it should be performed. Clinical follow-up is vital and must rule out symptoms and signs of heart disease and provide structured advice on heart-healthy behavior and regular physical exercise (Table 2).18 Special attention should be paid to the increased risk of the development of CVRFs and metabolic syndrome.80,81

Echocardiography is recommended for monitoring ventricular function (generally LVEF; GLS can provide added information in certain patients4), although there are no prospective data on the frequency of monitoring. Armenian et al.79 proposed that echocardiography be performed in survivors of childhood cancer 2 years after treatment and every 5 years thereafter, as well as cardiovascular follow-up before and after pregnancy.

In breast cancer survivors, echocardiography is recommended at the end of anticancer therapy to permit follow-up planning (if the LVEF and GLS are normal, the risk of HF is lower).14 Pathological findings should prompt treatment and periodic monitoring by a cardiologist.9,16 A cost-effective proposal is the combined algorithm of Carver et al.,82 which evaluates symptoms, echocardiography, and natriuretic peptides (Figure 10).

Figure 10.

Follow-up algorithm for patients with prolonged survival, modified from Carver et al.82 ECG, electrocardiography; ECHO, echocardiography; HF, heart failure; LVEF, left ventricular ejection fraction; NPs; natriuretic peptides; PE, physical examination. aMinor alterations in the ECG or intraventricular conduction disorder, nonsustained arrhythmias, or LVEF between 50% and 55%. bPatients with HF risk. cAny of the following conditions: age during treatment < 15 or > 65 years, female sex, any cardiac symptom or physical examination abnormality, cardiovascular risk factors, left ventricular dysfunction or previous heart disease, anthracyclines > 350mg/m2, chest radiation ≥ 35 Gy, combined treatment with anthracyclines and radiotherapy, premodern-era radiotherapy, follow-up > 10 years after treatment.

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For asymptomatic adult survivors with high risk of heart disease due to radiation, echocardiography should be performed after 5 years, ischemia testing at 5 to 10 years, and a reassessment every 5 years (Figure 3).19

The main recommendations for the cardiovascular care of patients with cancer are summarized in Table 6.