Report From the Cardio-Oncology Symposium at the Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO) Annual Congress

Overview of the meeting

The Cardio-Oncology Symposium at the Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO) Annual Meeting mainly focused on the diagnosis, management and prevention of cardiovascular toxicity of cancer drugs, in particular, cardiac dysfunction induced by anthracyclines. Although a variety of cardiac biomarkers and imaging modalities are available, there remains no consensus regarding their appropriate use to identify early and late cardiotoxicity and to guide preventive strategies. At the same time, the multitude of pharmacological trials, aimed at preventing cardiac damage through a neurohormonal blockade, provided conflicting results. Nevertheless, the advent of novel heart failure medications can change the decision-making of the cardio-oncologist. This symposium attempted to harmonize these issues.

Keywords:

• cardio-oncology
• cardiovascular imaging
• heart failure
• cardiotoxic drugs

The progress made in the field of cancer treatment has led to a dramatic improvement in the prognosis of oncologic patients. However, toxicities resulting from these treatments represent a cost that can endanger short- and long-term outcomes. Adverse events affecting the cardiovascular (CV) system are one of the greatest challenges in the management of cancer patients [1–3]. Such adverse events do not spare any component of the CV system and are associated not only with older chemotherapy drugs, such as anthracyclines, but also with many targeted therapies [1–3]. An emerging discipline, cardio-oncology, therefore, flourished with the aim of focusing on the pathophysiologic foundations and clinical correlates of cancer treatment-related cardiac dysfunction (CTRCD) [1–3]. The Cardio-Oncology Symposium at the Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO) Annual Meeting focused on early diagnosis of and management strategies for CTRCD.

The session, chaired by I Bisceglia and N Aspromonte, opened with a presentation by DM Cardinale from Milan, Italy. DM Cardinale remarked that over the past two decades, the role of cardiac biomarkers in diagnosing CTRCD, in particular troponins, has been the subject of a tough journey, starting in 2004 [4,5]. Considering they are inexpensive and largely reproducible and may reflect even minimal cardiomyocyte damage, circulating biomarkers have been investigated as potential early cardiotoxicity indicators [3,4]. Moreover, troponin modifications during chemotherapy allow for an accurate stratification of cardiac risk at the end of therapy: patients without an increase of troponin are not generally prone to developing left ventricular dysfunction and have a very low incidence of cardiac events [3–5]. On the other hand, patients who experience alterations in troponin, especially if the increase is persistent, have a higher probability of developing CTRCD [3–5]. Moreover, the opportunity to identify patients at risk of cardiac damage on the basis of biomarker monitoring offers the ability to start a targeted cardioprotective regimen. Enalapril, instituted after the first troponin rise and continued for a year, prevented the development of left ventricular (LV) dysfunction and cardiac events after chemotherapy. However, considering that troponin changes may occur at different points during chemotherapy administrations, frequently repeated blood samples may be necessary to identify its trend. In clinical practice, this may represent a limitation of the pharmacological preventive approach based on biomarkers fluctuations [5]. The aim of the International CardioOncology Society (ICOS)-ONE trial was hence to prospectively evaluate whether enalapril started in all patients prior to the beginning of chemotherapy could prevent troponin modifications and subsequent development of cardiac dysfunction, compared with a strategy based on biomarker alterations. Of the 273 patients enrolled and exposed to low cumulative anthracycline doses, at 1-year follow-up only 3 patients (1.1%) developed cardiotoxicity, defined as a 10% point reduction of LV ejection fraction (LVEF) with values <50%. No differences between the two enalapril strategies, preventive or troponin triggered, were observed. Nevertheless, enalapril is effective in protecting from LV dysfunction, without remarkable side effects [6]. DM Cardinale reminded us that the matter is even more tangled for natriuretic peptides. Evidence of their role comes from a limited study of 53 patients that showed that in patients who developed LV systolic dysfunction, a subclinical activation of the neurohormonal profile was observed. However, no other relevant data have emerged supporting their effectiveness as subclinical cardiotoxicity diagnostic tools. In a recent meta-analysis, no consistent association between an increase in BNP or N-terminal-proBNP (NT-proBNP) during chemotherapy and subsequent CTRCD development was found. However, it should be noted that BNP fluctuations during therapy, more than single values, were recently found to be useful markers of future cardiac dysfunction. In particular, BNP transient elevations accurately identified a population at high risk for CTRCD [7,8].

The second session was focused on cardiac imaging and was led by M Camilli (Rome, Italy) and P Pedrotti (Milan, Italy). The first analyzed the available evidence on echocardiographic markers of cardiotoxicity, starting with the definition of CTRCD. According to the 2016 European Society of Cardiology (ESC) Position Paper, a drop in LVEF of >10% points from baseline or <50% (considered the lower limit of ventricular function) identifies patients with cardiotoxicity. In contrast to LVEF, a measure of global longitudinal strain (GLS) provides information on LV subclinical systolic dysfunction. GLS is derived from ‘speckle tracking’ and can reliably assess the systolic performance of cardiomyocytes. Echocardiographic GLS has been recommended as a means to follow patients undergoing chemotherapy and at risk for CTRCD, defining a threshold drop of 15% to start cardioprotective therapies [3]. However, this role may be re-evaluated in light of the recent results of the SUCCOUR trial [9], which aimed to assess the value of medical intervention in response to changes in GLS. The total patients analyzed were 307, 154 subjects in the GLS surveillance arm versus 153 in the LVEF surveillance arm. Of patients in the LVEF surveillance group, 13.7% met the criteria for CTRCD versus 5.8% in the GLS group, so the incidence of predefined events was less in the GLS surveillance arm. This was an unexpected finding considering GLS is more sensitive than LVEF to cardiac dysfunction. Moreover, the primary end point was not met because of a statistically insignificant difference in LVEF between groups at 1-year follow-up. During the discussion, it was also noted that right ventricular impairment and diastolic dysfunction may represent common manifestations of early and late cardiac effects of chemotherapy [3,10,11].

Until the introduction of the HER2-targeted monoclonal antibody, trastuzumab, in the early 2000s, anthracyclines were the only drug class that required routine cardiac imaging prior to or during administration. Nowadays, many therapies, even those designed to be targeted, show CV side effects, starting from immune checkpoint inhibitors (ICIs), through proteasome inhibitors and the new frontiers of oncohematology, chimeric antigen receptor-T-cell therapies [1,3,12].

Cardiovascular magnetic resonance (CMR) provides information on cardiac structure, function and tissue characterization. CMR results are useful in answering many clinical questions in the emerging field of cardio-oncology [3,13]. P Pedrotti revised the principal indications of CMR in cardio-oncology services: it is useful for baseline risk assessment in patients with poor-quality echocardiographic images and for assessment in those with complex pre-existing heart disease or where vasodilator stress may be useful [13]. During follow-up, it is used for diagnosis of CTRCD and, thanks to the ability for tissue characterization, allows understanding of the pathophysiological mechanisms underlying cardiotoxicity. Moreover, CMR provides the possibility of establishing a definite diagnosis of myocarditis, in particular in subjects treated with ICIs [13]. Pericardial disease and valvular heart disease were other fields explored.

The current use of cardiac imaging in patients with cancer presents several challenges. First, there is a lack of clear recommendations for the monitoring of cardiac toxicities; routine cardiac imaging is essentially limited to patients with high basal risk, undergoing high doses of anthracyclines or an association with HER2-targeted therapies. Much less, if anything, is known about cardiac and cardiovascular injury associated with other classes of therapies. The discussant reminded attendees of two recently published expert consensus from the ICOS society [4,14] in which, based on the individualized risk of cardiotoxicity, an advised schedule of monitoring through imaging and biomarkers has been given for the majority of known cardiotoxic drugs. After all, the audience unanimously agrees on the fact that the monitoring of patients enrolled in clinical trials must expand beyond the traditional focus on a single value of LVEF as the only measure of cardiovascular complications related to chemotherapy. Echocardiographic assessment of myocardial strain (both atrial and ventricular) and diastolic dysfunction, together with tissue characterization through CMR, represent examples of advanced techniques ready for implementation in clinical practice.

The symposium was closed by ML Canale, who exposed the available evidence on cardioprotection [15]. As we know, primary preventive drug interventions are not recommended in patients without structural heart disease, cardiac risk factors or those not previously exposed to cardiotoxic agents/radiotherapy [3,15]. The path is paved toward a risk-based approach, including imaging parameters and circulating biomarkers. Nevertheless, the plethora of clinical trials on neurohormonal blockade compounds have provided conflicting results. The game seems changed since the introduction of novel heart failure agents, in particular sacubitril/valsartan (S/V), which is able to simultaneously inhibit the renin–angiotensin–aldosterone system (RAAS) and augment the endogenous vasoactive function of natriuretic peptides [16–18]. In a mouse model, S/V was first tested in the prevention of doxorubicin-induced myocardial dysfunction, providing encouraging results that paved the way for the now-enrolling PRADA II clinical trial [18]. As for S/V, another pharmacological class holds promise to subvert the cardioprotection scenario: sodium-dependent glucose cotransporter 2 inhibitors (SGLT2i) [19,20]. Few, but well-conducted, preclinical studies showed the efficacy of SGLT2-i in impeding LVEF drop during anthracycline exposure, independently of their diuretic and afterload reduction function. Even with limited evidence, the road toward the use of SGLT2i in clinical trials appears paved [21,22].

The key points of the symposium for clinicians were:

1.	To define in which subjects CV toxicity is more probable, adequately stratifying the patient’s basal risk;
2.	To define the most appropriate strategy to follow these patients, remembering advanced echo and CMR imaging techniques;
3.	To start pharmacological and nonpharmacological preventive strategies, keeping in mind available evidence and future perspectives;
4.	To train medical professionals at all levels to be aware of cardiotoxicity diagnosis and management.

Conference details

Title: Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO) Annual Meeting

Dates: 19–21 May 2022

Location: Rimini, Italy

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.