Introduction
Cardio-oncology is a frontier discipline that has existed for more than 2 decades, yet it is still a relatively young field. In recent years, changes in the epidemiology and leading causes of death have brought new scientific findings on cardiovascular and oncological diseases to focus (1). It has been recognised that the two groups of diseases have a significant overlap not only in their risk factors and pathomechanisms, but also in their other interplaying properties through complex signalling mechanisms. For these reasons, it is not uncommon for the two conditions to present in the same patient. In addition to the reasons listed above, this phenomenon is also partly explained by the fact that many different types of oncological treatments have the potential to induce cardiovascular adverse effects, classically known as cardiotoxic side effects. Thus, it is no coincidence that cardiotoxicity caused by anticancer treatments is one of the central issues in the field of cardio-oncology. These side effects may limit the success of oncotherapy and may also impair both the life expectancy and the quality of life of cancer patients. Several recommendations, statements and consensus documents have surfaced on this issue, providing various definitions of cardiotoxicity (2-6). A precise and accurate definition of cardiotoxicity is not only important for nomenclature, but also a major decision factor in the further treatment of oncological patients. It is therefore important to define cardiotoxicity, as its diagnosis may lead to the temporary suspension or even permanent discontinuation of ongoing oncotherapy. Early definitions of cardiotoxicity focused on classical cancer therapy-related cardiac dysfunction (CTRCD) as the main component of adverse events, distinguishing between two distinct examples: type I cardiotoxicity caused by anthracyclines, previously considered irreversible, but nowadays considered reversible, and type II cardiotoxicity caused by trastuzumab, which is thought to be reversible by default (7). Recent advances in scientific knowledge and the emergence of newer oncotherapeutic drugs necessitated the redefinition of this term, partly due to the recognition that various types of modern complex oncotherapy may lead to a wide range of cardiovascular complications, which are not limited to only myocardial dysfunction and heart failure. Various oncological treatments may, in some cases, cause coronary artery disease, hypertension, arrhythmias, valve disease, thromboembolism, pericardial abnormalities, not to mention the effects of newer oncological treatments such as immuno-oncological agents possibly leading to myocarditis, vasculitis or stress cardiomyopathy. In 2022, the European Society of Cardiology published the first evidence-based clinical practice guideline on cardio-oncology, which discusses in detail, among others, cardiotoxic side effects caused by oncotherapy, introducing a new definition of toxicity of anticancer therapy extended to the entire cardiovascular system (8). In this summary, we aim to provide a broader view of the various earlier concepts of cardiotoxicity, as well as its recent interpretation. This knowledge may help to ensure both the proper cardiovascular monitoring of patients receiving oncotherapy and the early detection and optimal management of potential adverse events.
Oncotherapy-induced cardiotoxicity – prior definitions
Over the last decades, a number of recommendations and consensus documents have been published in an attempt to provide guidance for the cardiological surveillance of oncology patients. For a long time, there were no sufficiently sensitive, uniform set of criteria for defining cardiotoxicity. In the early documents, the change in ejection fraction (EF) was considered the main determinant of CTRCD, but there was no consensus or well-defined cut-off value to support clinical decision-making. The cut-off between normal and abnormal EF was defined in some recommendations at 55% (9), in other documents at 53% (4,7) or even 50% (5). The degree of change in EF also differed in different papers, typically a 10% decrease was considered noteworthy. In a recent UK study, a 6-category toxicity classification, known as the Royal Brompton Hospital classification, was introduced (10). In this system, the determination of cardiotoxicity was fine-tuned by taking into consideration diastolic dysfunction, global longitudinal strain (GLS), symptoms, and possible changes in cardiac biomarkers, in addition to the EF. This was in line with the previous European position paper, which, among other points, also called for Simpson and 3-dimensional EF definition to avoid high intra- and interobserver variability, and the role of GLS and biomarkers to diagnose early, even subclinical impairment (5). By the 2020s, it has become clear that, despite several efforts, it is still difficult to obtain solid, evidence-based, prognostically valid data on cardiovascular parameters in oncology patients. However, well-defined cut-off values and the precise definition of cardiotoxic side effects are of great importance, since, apart from pharmacological aspects, they may determine the temporary or even permanent interruption of the patient’s anticancer treatment and thus, the clinical outcome of the underlying disease. The difficulty in collecting randomised data was mainly due to the very high heterogeneity of patients and disease courses, and also to the lack of standardised studies including large patient cohorts due to the diversity of treatments. However, over the years, more and more results have been presented from small-item prospective and medium-item retrospective observational analyses and registry data.
Redefining cardiotoxicity
CARDIOTOX registry
In 2020, one of the largest registries of cardio-oncology patient cohorts to date, called CARDIOTOX, was published (11), involving a total of 7 centres, mainly in Spain. The registry study, which used a two-year follow-up, included 865 patients undergoing oncotherapy with a moderate to high risk of cardiotoxicity. One of the major advantages of the registry was that it examined a large cohort of patients undergoing various treatments, and that individuals with mild to moderate cardiovascular disease were not excluded from the database unless they had manifest heart failure or a history of EF below 40%. Similarly, no previous cancer or cancer therapy was excluded. Consequently, the results from the registry were much closer to real-life data than before. The primary objective of the registry was to assess the risk of cardiotoxicity, to provide an early diagnosis of adverse events, and to determine the prevalence of clinical, biochemical and echocardiographic indicators of cardiotoxicity and their relationship to current heart failure criteria and treatment recommendations. A total of 865 of 1324 patients were included to form the final patient population. Those with incomplete data, heart failure or substantial EF reduction were excluded from the study. The registry was divided into 4 classes based on myocardial injury, dysfunction, symptoms, cardiac biomarker abnormalities and cardiac ultrasound parameters: 1) the normal group had no abnormalities in any of the studied parameters during the two-year follow-up, 2) the mild group included patients with no symptoms, an EF above 50% but elevated biomarker levels or other cardiac ultrasound abnormalities, 3.) the moderate category included asymptomatic patients with an EF between 40-50%, with biomarker elevation or other left ventricular dysfunction, 4) the severe category included asymptomatic patients with an EF below 40% or those with clinical signs of heart failure, with reduced, moderately reduced or preserved EF. Cardiotoxicity was defined as the onset of new or worsening myocardial damage or dysfunction when a patient was transferred from one class to a higher class during follow-up. After detailed analyses, cardiotoxicity was detected in about 37.5% of patients, with mild in 31.6% of cases and moderate or severe in 2.8% and 3.1% of cases, respectively. A slightly higher age was observed in the group with severe side effects. In terms of gender, most patients were women with breast cancer, of whom about 85% received anthracycline and 21% HER2 inhibitor treatment. Regarding cardioprotective therapy, 39% of patients were already taking one of the baseline drugs before the study, while this number increased to about 70% during follow-up. It was found that the risk of cardiotoxicity was increased if the patient had a history of previous cancer or oncological treatment, or a lower baseline EF and GLS. Based on the registry results, a 10% worsening of EF or a decrease in EF below 40% was relatively rare in the entire cohort, whereas increases in cardiac troponin and decreases in GLS were much more common. Survival of patients free from cardiotoxic side effects and those with mild to moderate side effects was significantly better compared to those with severe side effects (Figure 1). In summary, under the new definition of cardiotoxicity established in the CARDIOTOX registry study, transient or permanent myocardial dysfunction occurred in a relatively high percentage of patients; however, severe cardiotoxicity of strong prognostic relevance associating with increased mortality was relatively rare. It is necessary to reflect these findings in clinical practice, as they suggest that discontinuation of oncotherapy is most likely to be considered in the presence or prevention of mainly severe cardiovascular complications, the incidence of which is fortunately low. The classification into 4 classes is simple and easy to use, with mortality benefits mainly expected if patients susceptible to serious cardiotoxic side effects can be screened early. If we wish to diagnose cardiotoxicity with even transient myocardial injury or dysfunction at a subclinical stage, it is not sufficient to follow just the EF measured by conventional 2-dimensional echocardiography during the oncological treatment. In addition to routine examinations, the use of cardiac biomarkers and sophisticated echocardiographic parameters (3-dimensional EF, GLS, tissue Doppler) seems indispensable for the early detection of mild to moderate abnormalities.
Cardiovascular toxicity redefined in the clinical guidelines of the European Society of Cardiology
Recently, the first clinical guideline on cardio-oncology, already supported by levels of evidence and classes of recommendation, has been published under the auspices of the European Society of Cardiology in collaboration with several major international societies (8). The authors of this document have attempted to provide answers to a wide range of questions arising in daily practice during the cardiological management of patients receiving oncological treatment and cancer survivors. Among other things, algorithms for the risk classification of patients undergoing oncological treatment, additional clinical tasks according to risk stratification, expanded new definitions of cardiovascular toxicity, as well as recommendations for prevention, treatment and follow-up are included. The document continues to recommend the use of the previously used term CTRCD to refer to myocardial damage, myocardial dysfunction and heart failure associated with the oncological treatment. At the same time, the recently introduced international term CTR-CVT (cancer therapy-related cardiovascular toxicity) is proposed to define adverse events affecting any part of the cardiovascular system (12). CTR-CVT includes the 5 most common cardiovascular complications caused by anticancer therapy: 1) myocardial dysfunction and heart failure, 2) myocarditis, 3) vascular toxicity, 4) hypertension, 5) arrhythmias and corrected QT interval (QTc) prolongation. The definition of toxicity for each group is specifically detailed in the document, often with a strong emphasis on the severity of the abnormality and whether it is a symptomatic or asymptomatic adverse effect. In the case of myocardial dysfunction, a distinction is made between mild, moderate and severe but asymptomatic, while for symptomatic heart failure, the categories are mild, moderate, severe and very severe. These are differentiated on the basis of symptoms, EF, GLS, cardiac biomarkers, the need to consider intensification of therapy, the necessity of hospital setting, and in the most severe cases, the need for inotropic and/or mechanical circulatory support or cardiac transplantation (Table 1). In the case of myocarditis, the side effects of immune checkpoint inhibitor (ICI) treatments are of utmost importance. In the clinical diagnosis of myocarditis the presence of diagnostic characteristics of myocardial inflammation detected by cardiac MR imaging as major criteria, or the association of troponin elevation with two minor criteria plays an important role: clinical signs, ventricular arrhythmias and/or conduction disturbances, left ventricular systolic dysfunction with or without regional wall motion abnormality (non-Takotsubo type appearance), other immune-mediated complications (myositis, myopathy, myasthenia), suspected myocardial inflammation detected by cardiac MR. In terms of severity, ICI-induced myocarditis is differentiated into fulminant, non-fulminant and refractory to high-dose steroid treatment. Within the vascular toxicity group, asymptomatic atherosclerosis (coronary, peripheral, carotid), thrombosis (venous, arterial) and vasoreactivity disorder (peripheral, coronary macro- or microvasculature) are distinguished from symptomatic toxicity such as TIA/stroke, acute or chronic coronary syndrome, peripheral arterial vascular disease, vasospastic or microvascular angina, and the Raynaud’s phenomenon. Regarding hypertension, the need for temporarily suspending anticancer treatment is defined as blood pressure (BP) beyond 180/110 mmHg, otherwise, the control of BP with medication is recommended at values above 140/90 mmHg and 130/80 mmHg in patients at high cardiovascular risk. For arrhythmias, reference is made to the current European guidelines. In the QTc range of 480-500 ms, increased alert, correction of reversible causes, electrolyte replacement and discontinuation of other QT-prolonging agents are recommended, while for a QTc longer than 500 ms, discontinuation of therapy and consideration of dose reduction or alternative treatment is necessary.
| Symptomatic CTRCD | Very severe | HF requiring inotropic support, mechanical circulatory support, or consideration of transplantation |
|---|---|---|
| Severe | HF hospitalization | |
| Moderate | Need for outpatient intensification of diuretic and HF therapy | |
| Mild | Mild HF symptoms, no intensification of therapy required | |
| Asymptomatic CTRCD | Severe | New LVEF reduction to <40% |
| Moderate | New LVEF reduction by ≥10 percentage points to an LVEF of 40-49% OR New LVEF reduction by <10 percentage points to an LVEF of 40-49% AND either new relative decline in GLS by >15% from baseline OR new rise in cardiac biomarkers | |
| Mild | LVEF ≥50% AND new relative decline in GLS by >15% from baseline AND/OR new rise in cardiac biomarkers | |
| CTRCD = cancer therapy-related cardiac dysfunction; HF = heart failure; LVEF = left ventricular ejection fraction; GLS = global longitudinal strain (8) | ||
Future perspectives – precision medicine
From the above findings, it is clear that cardiovascular side effects from oncotherapy pose a great challenge to both clinicians and patients. The incidence and long-term effects of cardiovascular toxicity are difficult to predict and may be transient or irreversible. What further complicates the studying of adverse effects is the considerable variability between patients and the fact that adverse effects caused by different treatments induce various symptoms, which arise via different pathomechanisms. Precision medicine is gaining increasing attention in overcoming these challenges by personalising oncotherapy and thus, in preventing or alleviating cardiovascular toxicity. Precision medicine is a form of medicine that uses information about an individual’s own genes or proteins to prevent, diagnose or treat disease. Precision medicine proposes the tailoring of healthcare by recommending medical decisions, treatments, prevention strategies, care or drugs/products of choice to one or more individual subgroups of patients, avoiding a “one-size-fits-all” model (13). With the emergence of precision medicine platforms in oncology and cardiology, precision cardio-oncology has also become a necessary concept that takes into consideration the following three factors when treating patients: the patient’s cardiovascular risk, the tumour itself, and the oncology treatment plan. These can be used to predict with a good chance the occurrence and form of cardiovascular toxicity, which may improve the quality of cardio-oncology care (14). Estimating cardiovascular toxicity risk can be further aided by data from precision medicine, such as genetics, pharmacogenomics, proteomics and radiomics, which can be incorporated to characterise the cardiovascular biology of an individual. Precision cardio-oncology is also drawing increasing attention among basic researchers. A significant part of these research efforts involve the use of inducible pluripotent stem cells, which can be differentiated into cardiomyocytes to map the risk of cardiovascular toxicity from an oncological agent without the need for actual oncological therapy yet. This allows a more precise selection of safer oncological treatments with a lower cardiotoxicity index for a given patient, thus minimising the risk of cardiotoxicity. In addition, stem cells from larger populations may even be used to develop novel drugs and therapeutic options with a low cardiotoxicity index as a priority (15).
Conclusions
Cardio-oncology is a dynamic and evolving discipline with the main goal of promoting successful oncotherapy, long-term survival and improved quality of life for cancer patients. Over the past decades, a large body of knowledge has been accumulated in this field, which has helped to define the cardiovascular side effects of anticancer therapies more precisely, taking into account their role in clinical prognosis. A precise definition will greatly support appropriate therapeutic interventions and patient follow-up for better clinical prognosis. The recently redefined definition of cardiovascular toxicity takes into account both the severity of clinical abnormalities and the presence or absence of symptoms. The use of this new definition to detect adverse events and to assess a patient’s risk of cardiotoxicity may greatly improve the quality of cardio-oncology care and the long-term prognosis of patients.