Protecting the heart in cancer therapy

Introduction

Recent advances in cancer prevention and management have led to an exponential increase of cancer survivors worldwide¹. Regrettably, cardiovascular disease (CVD) has risen in the aftermath as one of the most devastating consequences of cancer therapies^2,3, being most prevalent in adult survivors of breast cancer and hematological malignancies^1,4,5.

In this work, we define cancer therapeutics-induced cardiotoxicity (CTIC) as the direct or indirect cardiovascular injury or injurious effect caused by cancer therapies, such as mediastinal radiotherapy⁶ and/or some chemotherapeutic agents⁷. These incipient toxic changes (e.g. cardiomyocyte apoptosis, cardiac ion-channel alteration, endothelial damage, etc.) can further develop into complex cardiovascular conditions, such as heart failure (HF), valvular heart disease, coronary artery disease (CAD), pericardial disease, systemic and pulmonary hypertension, arrhythmias, and thromboembolic disease, among others^8,9. Concomitant pre-existent cardiovascular risk factors have been shown to foment this pathogenesis¹⁰.

Pathogenesis of cancer therapeutics-induced cardiotoxicity

Stages of cancer therapeutics-induced cardiotoxicity

Patterned after an established classification of disease progression³¹, we have divided CTIC into four distinct stages, i.e. A, B, C, and D (see Figure 1). Stage A CTIC refers to cancer patients with cardiovascular health. Stage B CTIC designates cancer patients with high risk of developing CTIC. Risk factors for CTIC can be broadly divided into those pertaining to the patient and those pertaining to the cancer therapies implemented (see Table 2)^5,30,32,33. Stage C CTIC denotes “incipient” cardiotoxicity; this is the early stages of the cardiotoxic process before it becomes clinically apparent. This stage is characterized by the appearance of abnormal biomarkers that precede the clearly defined diseased entities (e.g. QTc prolongation precedes Torsade de Pointes and sudden cardiac death, and sarcomeric protein or natriuretic peptide serum elevations precede LV dysfunction and overt heart failure, etc.). Finally, stage D CTIC refers to established cardiotoxicity, which is manifested by cardiovascular syndromes in early or late stages, that requires standard diagnostic modalities and medical and surgical therapies derived from expert consensus guidelines^8,31,34–36.

Figure 1. Prevention of cancer therapeutics-induced cardiotoxicity.

Prevention of cancer therapeutics-induced cardiotoxicity.

Levels of prevention

Preventive strategies for CTIC can also be divided into four standard levels, i.e. primordial, primary, secondary, and tertiary, which correspond with the stages of CTIC; each level of prevention has a particular goal, focus, and means (see Figure 1).

Primordial prevention is principally focused on the education of both patients and providers and on the implementation of general best practices to impede the emergence and development of risk factors for CTIC. This is being accomplished by the explosion of expert consensus guidelines in the last decade (see “expert consensus guidelines” below) as well as a growing presence of cardio-oncology programs in major oncology and cardiology scientific meetings. Moreover, there has been an increasing number of continuing medical education materials and public health education programs in this topic, all serving to raise awareness and educate on the cardiovascular effects of cancer therapies. Furthermore, the International Cardio-Oncology Society and the Canadian Cardiac Oncology Network have recently partnered in the writing of a cardio-oncology multidisciplinary training proposal to formally educate physicians in this developing field³⁷.

Primary prevention has the goal of impeding the emergence of CTIC. The diagnosis and control of modifiable risk factors (see Table 2) and the promotion of cardiovascular health in the cancer population are of utmost importance. In addition, the administration of cardioprotective therapies to selected patients with unavoidable moderate and high risk of CTIC is a means of primary prevention (see “cardioprotectants” below).

Secondary prevention is enforced once cardiac toxicity is incipient; early diagnosis and surveillance (see “blood biomarkers and diagnostic modalities” below), implementation of cardioprotective strategies, and administration of cardioprotective and basic therapies have the overarching goal to mitigate the progression of cardiotoxicity, restore cardiovascular health, and prevent complications. As in most health conditions, earlier diagnosis and treatment of CTIC seem to translate into improved outcomes³⁸. Inspired by the American Society of Clinical Oncology (ASCO) clinical practice guideline on the prevention and monitoring of cardiac dysfunction in survivors of adult cancers⁵, as well as by other recent expert consensus guidelines that include recommendations on the prevention of CTIC^8,32,39,40, we have constructed a table summarizing the general evidence-based recommendations for the prevention of cardiotoxicity before, during, and after cancer therapies (see Table 3).

Lastly, once CTIC has progressed sufficiently to be manifest in cardiovascular syndromes (e.g. HF, arrhythmias, acute coronary syndromes, etc.), tertiary prevention aims to limit further progression and disability, and promote rehabilitation, by both basic and advanced cardiovascular therapeutics. The evaluation and management of these defined CTIC syndromes are similar to those encountered in non-cancer patients. There are several clinical practice guidelines for the evaluation and management of these conditions in the literature^{31,35,36,41,42}, and some specifically address the cancer population^8,9; these tertiary prevention strategies will not be further detailed in this work.

Expert panel consensus guidelines

As mentioned above, the prevention of cardiotoxicity induced by cancer therapies has increasingly been the focus of several clinical cardiovascular and oncological societies, demonstrating the increasing relevance that this field has taken in the latest decade. In 2012, the European Society for Medical Oncology published a basic set of clinical practice guidelines for the prevention, monitoring, and management of CTIC⁴⁰. The American Society of Echocardiography and the European Society of Cardiovascular Imaging joined forces to create expert consensus guidelines for the multimodality imaging evaluation of cardiovascular complications of radiotherapy in adult patients in 2013³⁰ as well as evaluation during and after cancer therapies in 2014⁴³. These efforts aim to standardize the indications, acquisition protocols, definitions, limitations, and vendor variability for the different cardiac imaging modalities usually employed in the diagnosis and surveillance of CTIC. In 2016, the American Heart Association (AHA) released a comprehensive scientific statement describing the mechanism, magnitude, onset, and likelihood of direct myocardial toxicity of several anti-cancer medications, among other clinically approved drugs, “to assist healthcare providers in improving the quality of care for these patients”⁷. In the same year, the Canadian Cardiovascular Society published a set of best practice guidelines for the management of cancer patients, focusing on the identification of the high-risk population and the detection and prevention of cardiotoxicity³⁹. This was followed by a position paper from the European Society of Cardiology summarizing the available evidence on the pathophysiology, prevention, diagnosis, therapeutic management, and long-term surveillance of the most common forms of cardiotoxicities induced by cancer therapies⁸. Most recently, as mentioned above, the ASCO published a clinical practice guideline outlining general recommendations for the prevention of cardiac dysfunction in survivors of adult cancers⁵. It was developed by an expert multidisciplinary physician panel using a systematic review (1996–2016) of 104 articles (meta-analyses, randomized clinical trials, and observational trials) and their clinical experience. Finally, the AHA has just published a scientific statement specifically and comprehensively dealing with the prevention of CVD in breast cancer patients, including that caused by cancer therapies³².

Cardioprotectants

The development and investigation of cardioprotective agents has been exponentially increasing since the early days of anthracycline cardiotoxicity. To date, only one cardioprotectant is approved for clinical use, i.e. dexrazoxane; many others have been tested in the clinical setting, and an even larger number are on preclinical stages of investigation (see Table 4 for a succinct list of cardioprotective agents for CTIC that have been shown to be useful at different stages of research). The vast majority of cardioprotectants have been tested in the setting of anthracycline administration, either alone or in combination with other chemotherapeutic agents; a small number has been tested in trastuzumab-only administration.

Blood biomarkers

Blood biomarkers, in particular myocardial natriuretic peptides (i.e. NTproBNP and BNP) and sarcomeric proteins (i.e. troponin I and T), have been an integral part of the diagnostic and prognostic armamentarium in common cardiovascular conditions, such as HF and CAD. As it would seem natural, they have been progressively adopted in clinical practice to assist in the diagnosis or surveillance of patients with incipient and established CTIC, in particular LV dysfunction and HF (see Table 5 for a list of various clinical and preclinical biomarkers shown to predict CTIC)⁵.

Troponin I^59,116,117 and troponin T¹¹⁸ have been shown to be clinically useful in several clinical trials of cardiotoxicity prediction. Modern, more-sensitive assays of troponin I and T (high-sensitivity and ultra-sensitivity) have also been shown to be clinically predictive of CTIC^121–123. Early studies have suggested that troponin I elevation predicted severity of CTIC^116,117, and refractoriness to HF therapy in the case of trastuzumab-induced cardiomyopathy¹¹⁷, but response to enalapril monotherapy in the case of AIC⁵⁹. However, in a recent large multicenter randomized clinical trial, these findings could not be corroborated¹⁰³. Interestingly, the presence of troponin-specific autoantibodies also predicted cardiac dysfunction by cardiac magnetic resonance (CMR) imaging in the absence of elevated traditional troponin levels¹²⁴. Myocardial natriuretic peptides, such as NTproBNP¹¹⁹, BNP¹⁴⁷, and ANP¹²⁰, have also been shown to be clinically useful predictors of CTIC, albeit to a lesser extent.

Although the use of these blood biomarkers is currently recommended in the evaluation and surveillance of patients with CTIC^5,8, their helpfulness remains disputed owing to inconsistent results in terms of sensitivity, accuracy, and reliability¹⁴⁸. Hence, various other alternative blood biomarkers have been studied in recent years, either alone or in combination, and shown also to be clinically predictive of CTIC, e.g. hsCRP¹²⁶, MPO¹²³, and arginine-NO metabolites (arginine, citrulline, ornithine, asymmetric dimethylarginine, symmetric dimethylarginine, and N-monomethylarginine)¹²⁹, among others^{125,127,128,130–132}. Likewise, many other predictive biomarker strategies are currently being developed in the preclinical arena. Proteomics¹⁴⁴ and metabolomics¹⁴⁵ pattern diagnostics, as well as transcriptome profiling¹⁴⁶, have been shown to be useful in animal models of AIC as well as the detection of doxorubicin DNA adducts (HM-dUMP, 8-OH-dGMP, HM-dCMP, and Me-dCMP)¹³⁶ and other particular genes that are overexpressed during incipient cardiotoxicity¹³⁷. Cellular proteins such as S100A1¹⁴¹, cMLC1¹⁴², and cathepsin B¹⁴³ have also been shown to have predictive value. Some microRNAs (e.g. miR-34a¹³⁸, miR-34c¹³⁹, and miR-146a¹⁴⁰) have been shown to be useful in predicting CTIC in small animal models; however, a recent clinical trial involving miR-208a measurement in breast cancer patients failed to have a predictive impact¹⁴⁹.

Finally, research efforts to identify the genetic susceptibility of AIC have been increasing in the last decade, with the purpose of risk stratifying patients before they receive anthracycline chemotherapy. To date, three main single-nucleotide polymorphisms (SNPs: rs28714259¹³⁵, rs1786814¹³⁴, and rs2229774¹³³) have been identified as being strongly associated with AIC by means of genome-wide association studies (GWAS) from pediatric and adult case-controlled clinical trial populations.

Diagnostic modalities

Non-blood diagnostic modalities are also an integral part of the evaluation of CVDs. For the purpose of early diagnosis and surveillance of CTIC, several imaging modalities have been studied since the late 1970s and shown to be of value (see Table 6). Historically, electrocardiography¹⁵⁰ was used to diagnose arrhythmias during anthracycline infusion, and radionuclide cineangiography (MUGA)^151,152 was the first technique used to detect falls in LV systolic function in patients receiving anthracyclines¹⁵³. Although MUGA is still considered widely available and highly reproducible, it carries the main disadvantage of submitting cancer patients to small, but potentially significant, radiation exposure (5–10 mSv)^30,43. Additionally, 2D-echocardiogram¹⁵⁴ and stress 2D-echocardiogram¹⁵⁵ have been shown to be beneficial in the serial evaluation of cancer patients undergoing cardiotoxic chemotherapies. Newer echocardiographic modalities, such as 3D-echocardiography¹⁵⁶ and LV global longitudinal strain (LVGLS) measurement by speckle-tracking echocardiography (STE)¹⁵⁷, have demonstrated superiority over 2D-echocardiography in terms of reproducibility and predictability, respectively. CMR is currently considered the gold standard modality in the assessment of LV and right ventricular volumes and function¹⁵⁸. Secondary modalities such as CMR strain imaging¹⁵⁹, T1 mapping¹⁶⁰, and extracellular volume fraction (ECV)¹⁶¹ have also been clinically studied in recent years and found to be of great value in the assessment of subclinical cardiotoxicity. Among various non-imaging techniques, cardiopulmonary exercise testing was shown to detect abnormalities in peak oxygen consumption in cancer patients with apparently normal LV function¹⁶², suggesting subclinical impairments of contractile reserve and chronotropic incompetence²⁸. Finally, many other imaging modalities are currently being studied in the preclinical arena to help detect incipient cardiotoxicity with high specificity and sensitivity. For example, 18F-labeled tetrapeptide caspase positron emission tomography (PET) is able to specifically diagnose doxorubicin-induced myocardial apoptosis in a murine model by detection of overexpressed myocardial caspase 3 resulting from anthracycline chemotherapy¹⁶³.

According to current guidelines, echocardiography (ideally 3D-echocardiography) is the method of choice for the evaluation of patients before, during, and after cancer therapies⁴³. CMR and MUGA scan (in that order) should be utilized as alternative modalities whenever the echocardiographic image quality is deficient⁵. When available, measurement of LVGLS by STE is also recommended as a complementary modality⁵. CMR should also be considered for the evaluation of chronic “constrictive” pericarditis, when the diagnosis remains uncertain after a careful echocardiographic evaluation⁴³.

To date, there is little evidence to guide the indication, timing, and frequency of use of imaging modalities in patients undergoing cancer therapies. The ASCO expert consensus recommends an echocardiographic evaluation prior to the initiation of potentially cardiotoxic cancer therapies⁵. Routine imaging surveillance in asymptomatic patients should be offered to patients based on the healthcare provider’s perceived risk of CTIC, and the frequency of it needs to be individualized based on clinical judgment and patient circumstances⁵. Subsequent to cardiotoxic cancer therapies, it is recommended that high-risk patients undergo a follow up LVEF evaluation between 6 and 12 months after completion of therapy⁵.

Conclusions

In this work, we have attempted to comprehensively and concisely survey the most relevant available literature pertaining to cardioprotection during cancer therapy. We have briefly summarized the pathophysiology of CTIC, describing the mechanisms of cardiotoxicity of various agents, and risk factors that promote this phenomenon. For didactic purposes, we have classified CTIC into four progressive stages, in which four levels of prevention are applied, each having a specific goal, focus, and means of prevention. We have subsequently reviewed the available data on cardioprotective agents, blood biomarkers, and imaging diagnostic modalities, which are the core of primary and secondary prevention strategies. Finally, we have provided general evidence-based preventive recommendations for CTIC following the most current expert consensus guidelines. The promotion of the cardiovascular health of cancer patients and cancer survivors is paramount, requiring the diligent and knowledgeable effort of a multidisciplinary team of healthcare providers; as in all medical disorders, prevention is better than cure.