Cardiotoxicity of antineoplastic therapy – underlying mechanisms, clinical manifestations, and basic principles of cardio-oncology

Malignancies and cardiovascular diseases are the most common cause of morbidity and mortality in the modern world. Taking into account the ageing population of developed countries and the fact that malignancies are mainly diseases of old age, the projected increase in the incidence of malignancies in the countries of the European Union, by 2040, is more than 20%. Modern, personalized therapy of malignant diseases, which has significantly improved the prognosis and survival of hemato-oncology patients, requires careful ambulatory patient follow-up, in order to prevent, timely diagnose and adequately treat the immediate and delayed adverse effects of antineoplastic therapy. The cardiovascular system is particularly sensitive to antineoplastic agents due to its particular structure and functions. A personalized and multidisciplinary approach in the treatment and follow-up of hemato-oncology patients has led to the development of a new subspeciality – cardio-oncology, whose main task is the early identification of oncological patients, with or without associated cardiovascular disease, who have an increased risk of developing cardiotoxicity during antineoplastic treatment. The article describes the basic mechanisms of cardiotoxicity of the most important groups of antineoplastic drugs, clinical manifestations as well as contemporary recommendations for primary and secondary prevention.

INTRODUCTION

Modern treatment of malignant diseases has significantly improved the prognosis and survival of hemato-oncology patients [1]. In the past forty years, the ten-year survival of patients with non-Hodgkin lymphomas has increased from 20% to over 65% [2]. In addition, malignant diseases are the leading cause of premature mortality (death of people under 70 years of age) in developed regions of the world [3]. Taking into account demographic changes, i.e., the ageing of the population in developed countries, as well as the fact that malignant diseases are mostly diseases affecting the elderly, the projected increase in the number of patients in EU countries, by 2040, is over 20% [4]. As elderly people often have associated diseases, i.e., comorbidities, a multidisciplinary approach to treatment, as well as improving the quality of life of patients, are the basis of the Geriatric Oncology Program implemented by the European Organisation for Research and Treatment of Cancer (EORTC) [5].

Oncological treatment often involves simultaneous or successive application of agents with different mechanisms of action in order to potentiate the antineoplastic effect. Targeted therapy with monoclonal antibodies (MABs), as well as with small molecules administered orally, such as tyrosine kinase inhibitors, often involves continuous treatment until disease progression [6]. Tables 1, 2, 3 and 4 list the most important groups of antineoplastic drugs, according to the World Health Organization classification (available at: https:// www.whocc.no/atc_ddd_index/), and their mechanisms of action [7],[8],[9],[10],[11]. The contemporary approach to the treatment of patients with malignant diseases, in addition to personalized innovative therapy that significantly contributes to its success, but also to the shortening of hospital treatment, also includes careful outpatient monitoring of hemato-oncology patients, in order to prevent, timely diagnose and adequately treat immediate and delayed side effects of antineoplastic treatment.

Table 1. Classes of antineoplastic drugs

Table 2. Tyrosine kinase inhibitors

Table 3. Hormones, hormone antagonists and other antineoplastic drugs

Table 4. Tyrosine kinase inhibitors

Complications arising from the application of conventional chemotherapy (CT), radiation therapy (RT), hematopoietic stem cell transplantation (HSCT), and targeted therapy are complex and multifactorial. They can be viewed from several different aspects:

1. dysfunction of organs and systems of organs
2. premature death
3. development of secondary malignancies
4. delayed growth and development
5. intellectual impairment
6. reduced fertility
7. reduced quality of life
8. socioeconomic aspect [12].

CARDIOTOXICITY AND CARDIO-ONCOLOGY

Cardiovascular diseases (CVD) are, together with malignant diseases, the most widespread diseases in developed countries, while the cardiovascular system (CVS) is, given the specificity of its structure and function, particularly sensitive to antineoplastic therapy. Also, certain malignancies, due to their localization (e.g., lungs, mediastinum) and their natural progression, affect the CVS, independently of treatment. A personalized and multidisciplinary approach to the treatment and monitoring of hemato-oncology patients has led to the development of a new subspecialty – cardio-oncology, whose main task is the early identification of oncology patients, with or without associated cardiovascular diseases, who have an increased risk of cancer therapy-related cardiovascular toxicity (CTR-CVT), as well as the timely planning and implementation of diagnostic and therapeutic cardiology procedures that will be carried out during and after the completion of oncological treatment, in order to improve patient survival and quality of life [13].

Therefore, a careful assessment of cardiac function is necessary when making a decision on the type of antineoplastic therapy, but also during its application, as well as years after the completion of hemato-oncology treatment. The International Cardio-Oncology Society (IC-OS) defined the basic postulates of CTR-CVT [14]. In 2020, the European Society for Medical Oncology (ESMO) issued the first recommendations for the prevention, early diagnosis, monitoring, and treatment of CTR-CVT [15], and in 2022, comprehensive cardiooncology guidelines created on the basis of a consensus amongst experts of the European Society of Cardiology (ESC), the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESC), the European Society for Therapeutic Radiology and Oncology - ESTRO) and IC-OS, were published [16].

MECHANISMS OF MYOCARDIAL DAMAGE CAUSED BY ANTINEOPLASTIC THERAPY

Antineoplastic therapy can lead to irreversible damage to the myocardium (Type I), or to cardiomyocyte dysfunction, i.e., reversible myocardial damage (Type II) [17]. Irreversible myocardial damage is most often caused by anthracyclines, while reversible myocardial damage is a characteristic of HER-2 (human epidermal growth factor receptor 2) and VEGFR (vascular endothelial growth factor receptor) inhibitors, as well as of BCR-ABL tyrosine kinase inhibitors [18].

The main types of cell death that occur as the result of CTR-CVT are autophagy, apoptosis, ferroptosis, pyroptosis and necroptosis. Cardiomyocytes are very rich in mitochondria, whose main function is to generate energy (ATP-adenosine triphosphate) in the process of oxidative phosphorylation. The most important mechanism of irreversible cardiotoxicity of anthracyclines is the increased generation of oxygen free radicals (reactive oxygen species - ROS) during the reduction of doxorubicin to doxorubicinol under the influence of flavoenzymes in the presence of oxygen (oxidative stress), to which mitochondria are especially sensitive, as is the cell membrane, other organelles (endoplasmic reticulum), as well as the nuclear membrane and DNA. Damage to mitochondrial membranes leads to the activation of the autophagy signaling protein ULK-1 (unc-51 like autophagy activating kinase 1), and to the binding of mitochondria to autophagosomes and their transport to lysosomes, where they undergo degradation. Under physiological conditions, mTOR (mammalian target of rapamycin) inhibits ULK-1. Doxorubicin, in addition to damaging mitochondria, inhibits mTOR by promoting autophagy. Damage to mitochondrial membranes through ROS leads to the release of cytochromes and activation of proapoptotic caspase-3, while doxorubicin induces apoptosis by activating the tumor suppressor gene p53. Apoptosis is significantly potentiated when HER-2 inhibitors are administered simultaneously with doxorubicin. Doxorubicin also affects the RNA of the regulatory protein ferritin and iron (iron regulatory protein - IRP), leading to a decrease in the concentration of ferritin and an increase in the concentration of free iron in cells. In the presence of free iron, the generation of ROS from lipid peroxides is significantly higher, causing ferroptosis. Caspase-1 activation leads to the release of pro-inflammatory cytokines (interleukin (IL)-1 and IL-18) and pyroptosis. By activating the TNF (tumor necrosis factor) signaling pathway, doxorubicin causes necroptosis (cytokine-mediated necrosis). Damage to the endoplasmic reticulum leads to a decrease in protein-bound calcium in cells and a consequent decrease in myocyte contractility. On the other hand, free Ca²⁺ damages myofibrils by activating proteases. Also, the binding of doxorubicin to nitrogen monoxide (NO) synthetase in the endothelium causes reduced synthesis of nitrogen monoxide, a very important endogenous vasoactive substance. These processes are not only characteristic of the myocardium, but, unlike other tissues, the myocardium contains very few catalases that inactivate free radicals [5],[18]. Forty genes, whose polymorphism contributes to anthracycline cardiotoxicity, have been detected, but genetic testing is still not recommended [19].

Irreversible myocardial damage is dose-dependent [20]. The recommended maximum cumulative doses of some conventional cytostatic agents in adult patients are, as follows: doxorubicin – 550 mg/m² (if applied in chemotherapy cycles every 21 days), with cardiological monitoring at cumulative doses higher than 300 mg/m² ; daunorubicin – between 400 and 550 mg/m² ; epirubicin – 900 mg/m² ; idarubicin – 150 mg/m² ; mitoxantrone – 140 mg/m² ; while cyclophosphamide in a single dose >150 mg/kg (or 1.55 g/m²/d), administered during HSCT, can lead to sudden cardiac death [18].

CLINICAL MANIFESTATIONS OF CTR-CVT

According to the time of occurrence, CTR-CVT can be early, which occurs during the hemato-oncology treatment itself, and late, which manifests years after the end of the treatment of malignant diseases. Clinically, CVS damage is manifested by the appearance of the following:

• heart failure (HF)/cardiac dysfunction
• arterial hypertension
• prolonged QT interval and arrhythmias (supraventricular arrhythmias, ventricular arrhythmias, bradycardia, atrial fibrillation/flutter)
• myocarditis/pericarditis
• vascular disorders (arterial and venous thrombosis) [14],[15],[16],[17].

Table 5 lists the drugs that most commonly lead to certain clinical manifestations of CTR-CVT.

Table 5. Clinical manifestations of cardiotoxicity and the antineoplastic drugs that are most commonly their cause

The following patient characteristics particularly indicate an increased risk of CTR-CVT:

1. previous antineoplastic therapy (administration of anthracyclines, concomitant or successive administration of anthracyclines and HER-2 inhibitors, previous RT of the chest and mediastinum)
2. age (persons above the age of 75 and below the age of 10)
3. smoking status (active and former smokers) and obesity (BMI > 30 kg/m²)
4. comorbidities: diabetes (HbA1c > 7.0% or > 53 mmol/mol), chronic kidney failure (Egfr < 60 ml/min/1.73 m²), dyslipidemia (non-HDL cholesterol > 3.5 mmol/l)
5. cardiovascular status: arterial hypertension (systolic pressure > 140 mmHg, diastolic pressure > 90 mmHg), elevated level of cardiospecific enzymes before starting treatment, left ventricular ejection fraction (LVEF) < 50%.

Based on the above-described factors, all patients are classified into the following three groups: patients with low risk, patients with medium risk, and those with moderately high or high risk of developing CTR-CVT [15],[16].

DIAGNOSTIC PROCEDURES IN PRIMARY AND SECONDARY PREVENTION OF CTR-CVT

Before administering antineoplastic therapy, it is necessary for all patients to have an electrocardiogram (ECG). Prolongation of the QT interval (> 500 ms) is the first sign of myocardial repolarization disorders and of the possibility of fatal arrhythmias, especially if they are associated with electrolyte imbalance (low concentrations of potassium, magnesium and calcium) or with the concomitant use of certain antibiotics and antiemetics.

Transthoracic 3D echocardiography (TTE) is also a standard procedure that is performed before starting any oncological treatment and during which the left ventricular (LV) function, right ventricular (RV) function, dilatation of cardiac chambers, left ventricular hypertrophy, regional contractility disorders, diastolic function, valvular defects, pulmonary artery pressure, and the condition of the pericardium, are evaluated. LVEF > 50% is considered safe. Patients with increased risk must be monitored regularly with echocardiography. Any decrease in LVEF ≥ 10% or decrease in global longitudinal strain (GLS) > 15% indicates myocardial dysfunction [21]. In cases where TTE findings cannot be adequately interpreted, cardiac magnetic resonance imaging should be performed [16].

In oncology patients with cardiovascular disease, it is necessary to determine the cardiac markers: high-sensitivity troponin I (hs troponin I) as well as natriuretic peptides (NP) – B-type NP (BNP) and N-terminal pro-BNP (NT-proBNP), before starting treatment, and to monitor them regularly during hemato-oncology treatment, especially during the administration of anthracyclines. Early increase in hs troponin I > 99^th percentile, BNP ≥ 35 pg/ml, and pro-BNP ≥ 125 pg/ml, during the use of antineoplastic therapy, indicates the development of CTR-CVT [14],[15],[16].

Dexrazoxane and liposomal forms of conventional cytostatic agents are the only drugs approved for the prevention of CTR-CVT, primarily heart failure caused by anthracyclines. Dexrazoxane, an iron chelator and topoisomerase I inhibitor, is officially approved for use in breast cancer patients who are at high risk of CTRCVT and who have previously received a cumulative dose of doxorubicin of at least 300 mg/m2 (or anthracycline equivalent). Intravenous infusion of dexrazoxane is administered 30 minutes before each cycle of chemotherapy protocol containing anthracyclines, in a dose of 10:1 (e.g., 500 mg dexrazoxane : 50 mg doxorubicin) [22]. However, its use may be associated with a reduced response to antineoplastic therapy as well as an increased incidence of secondary malignancies [18].

In patients with high CVR-CVT, liposomal forms of conventional cytostatic agents are also administered – pegylated or non-pegylated liposomal daunorubicin, or a fixed combination of liposomal daunorubicin and cytarabine, which has been approved for the treatment of acute myeloid leukemia [23].

For primary prevention of CTR-CVT in high-risk patients, the use of angiotensin-converting enzyme (ACE-I) inhibitors, angiotensin receptor blockers (ARBs), as well as statins, is recommended [16]. It has been proven that patients with malignant diseases, especially in advanced stages and with more aggressive histological types, have a lipid profile disorder [24, 25], and statins, in addition to their cardioprotective effect, also have an antineoplastic effect, causing apoptosis of malignant cells [26, 27].

It is very important to emphasize that many conventional and novel antineoplastic drugs have pronounced interactions with other drugs (e.g., antiepileptics, antipsychotics, drugs metabolized by cytochromes, drugs that affect gastric pH), as well as with food (e.g., grapefruit juice), which can cause a disruption in the resorption, metabolism, and excretion of the antineoplastic drug, and therefore its reduced/increased concentration in the body, which affects not only the drug’s antineoplastic effect but also carries the risk of toxic effects, including CTR-CVT. Therefore, it is necessary to inform the patient, in detail, about all possible side effects of concomitant therapy and the necessity of strictly observing the time sequence of drug intake [16].

In secondary prevention, i.e., in patients who have an associated CVD or CTR-CVT, which manifested during previous or current hemato-oncology treatment, regular clinical follow-up is necessary, including the follow-up of cardiac biomarkers, 12-channel ECG, and TTE, together with appropriate therapy. Follow-up and therapeutic approach protocols in secondary prevention of CTR-CVT have been defined for the most commonly used groups of antineoplastic agents, for the most common drug combinations used in the treatment of certain malignant diseases (multiple myeloma, prostate cancer, breast cancer), for radiotherapy (RT), as well as for hematopoietic stem cell transplantation (HSCT). Depending on the severity of manifested CTR-CVT, antineoplastic therapy can be continued or temporarily or permanently discontinued [15],[16].

DRUGS USED FOR SECONDARY PREVENTION DEPEND ON THE CLINICAL MANIFESTATION OF CTR-CVT

• For the treatment of new-onset cardiac dysfunction/HF, ACE-I, ARB and/or beta blockers are used, with initial regular TTE check-ups every 2 – 3 weeks during antineoplastic therapy (if its continuation is not contraindicated), as well as 6 and 12 months after the completion of hemato-oncology treatment.
• For the treatment of myocarditis, which, in recent years, has been most commonly caused by immune checkpoint inhibitors of programmed cell death protein 1 (PD-1) and programmed death-ligand (PD-L1), corticosteroids are recommended. Initial therapy for fulminant forms, which require hospital treatment, is methylprednisolone at a dose of 500 – 1,000 mg/d IV, for three days, then prednisone 1 mg/kg, with a tapering of 10 mg/week to a dose of 20 mg/day, and after that slow reduction of the dose by 5 mg/week, with regular monitoring of troponin. In corticosteroid-resistant patients, mycophenolate mofetil, antithymocyte immunoglobulin, tocilizumab, abatacept, alemtuzumab, therapeutic plasma exchange, and Janus kinase 2 (JAK-2) inhibitors, can be used as second-line treatment [28].
• The treatment of acute coronary syndrome which develops during active hemato-oncology treatment is very complex. Malignant diseases represent a chronic proinflammatory and prothrombogenic state, and the expected hematological complications accompanying antineoplastic therapy (anemia, thrombocytopenia, febrile neutropenia) limit the possibility of optimal treatment, especially the possibility of applying antiplatelet therapy and surgical procedures [16]. In case of thrombocytopenia of < 20x10⁹/l, it is advised to administer platelet (PLT) transfusions before catheterization, and to apply the radial approach with careful hemostasis and low doses of heparin (30 – 50 U/kg). Aspirin is discontinued when the platelet count is PLT < 10x10⁹/l, clopidogrel is discontinued at PLT < 30x10⁹/l, and prasugrel and ticagrelor are discontinued at PLT < 30x10⁹/l. The recommended minimum platelet count for percutaneous coronary intervention (PCI) is 30x10⁹/l, and for coronary artery bypass grafting (CABG) 50x10⁹/l [29].
• Venous thromboembolism (deep vein thrombosis and pulmonary embolism) is treated with anticoagulation therapy, in keeping with the protocols, with dose modification depending on the number of platelets. Individual thrombogenic risk can be assessed using clinical scores (Khorana, Padua, Caprini), taking into account comorbidities, laboratory parameters, as well as the type of malignancy. Neoplasms with the highest prothrombogenic risk are stomach and pancreatic cancer, while lung, kidney, testicular, and urinary bladder cancer, gynecological malignancies, as well as lymphomas, carry a high risk of venous thrombosis. During active oncological treatment, the use of low-molecular-weight heparin is recommended. The use of direct oral anticoagulants (DOACs), apixaban, rivaroxaban and edoxaban, may increase the risk of bleeding as these are potent inhibitors of cytochrome P450 (CYP3A4 subtype) and/or P-glycoprotein (P-gp), and particular caution is required when these drugs are concomitantly administered with conventional cytostatic agents (anthracyclines, alkylating agents), monoclonal antibodies and small molecules. Antineoplastic drugs also affect the concentration of warfarin, which is metabolized via CYP2C9 and can either lead to an increased risk of bleeding (pyrimidine antagonists, some anthracyclines, obinutuzumab, pegylated interferon alfa 2a, Bruton’s kinase inhibitors, BCR/ABL kinase inhibitors) or, by the induction of CYP2C9, they can lead to reduced warfarin concentration and increase the risk of thrombosis (purine analogues, plant alkaloids, estrogens, anaplastic lymphoma kinase (ALK) inhibitors) [16],[30].

CONCLUSION

Malignant diseases and CVDs are the most common causes of morbidity and mortality in modern society. Prevention, timely diagnosis and appropriate treatment of CTR-CVT, caused by the application of conventional and modern antineoplastic therapy, require a multidisciplinary approach. This is what has led to the development of cardio-oncology, as well as to the development of common hemato-oncology-cardiology guidelines, with the aim of achieving longer survival and a better quality of life for patients.