Thirty years after treatment, as many as one in eight survivors of childhood cancer treated with anthracyclines and chest radiotherapy (RT) will develop a life-threatening CVD, and the likelihood increases as survival progresses. Exposure to doxorubicin at doses ≥250 mg/m² and to ≥15 Gy of chest RT is considered as a high-risk condition, as it increases the relative risk of heart failure as well as pericardial and valvular disease by 2- to 5-fold compared to non-exposure (32). The recent reduction in the incidence of coronary artery disease (CAD) in children with cancer is due to the greater attention paid to limiting cardiac exposure to RT (33). Cancer treatment is also associated with the risk of developing comorbidities, and 40% of childhood, adolescent and young adult CSs have multiple comorbidities 10 years after the index date. Childhood, adolescent and young adult CSs also have an increased risk of cardiomyopathy, stroke, premature ovarian failure, chronic liver disease, thyroid disorders, diabetes, hearing loss and renal failure (34).

Older women with breast cancer have a higher risk of dying from CVD than controls. Thus, according to the “multiple-hit” hypothesis (35) the main effort should be directed at reducing a high CV risk profile worsened by cancer treatment. An assessment of the CVD risk within the first year after completion of cardiotoxic cancer therapy can identify CSs who require long-term surveillance. Patients with high/very high baseline CVD risk factors and those who develop ventricular dysfunction at the end of treatment are at high risk of CVD during the first 2 post-treatment years (“early” high risk), while patients treated with high doses of anthracyclines plus RT or with poor control of cardiovascular risk factors (CVRFs) are at high risk of late CVD (“late” high risk). The ESC guidelines on CO provide recommendations for survivors of childhood and adolescent cancer and for adult CSs (29) (Table 2).

New treatment approaches are changing the natural history of many cancers, including metastatic breast (36), prostate (37), lung cancer (38), lymphomas (39) and other common cancers, while also increasing the risk of CVD-related death or disabilities (40, 41). A decline in adherence to prescribed cardiovascular drugs has also been reported (42).

Cardiac troponin and natriuretic peptide are the most extensively evaluated cardiac biomarkers. Both have been used to investigate the cardiac toxicity of anthracyclines and HER2-inhibitors, whereas their utility in patients treated with other anticancer drugs (43, 44) and the value of their routine use in patients undergoing potentially cardiotoxic treatment are thus far unclear. According to the European Society for Medical Oncology guidelines, baseline measurements of cardiac biomarkers should be considered for high-risk patients (i.e., those with preexisting significant CVD) and those receiving high doses of cardiotoxic chemotherapy such as anthracyclines (45). The recently published ESC guidelines on cardio-oncology recommend the use of natriuretic peptide and/or troponin before anticancer therapy in all cancer patients at risk of CTR- CVT if these biomarkers are going to be measured during treatment to detect CV toxicity (class I, level C recommendation) (29). Baseline biomarkers may indeed allow the identification of those patients most likely to benefit from cardio-protective therapy. A potential prognostic role of troponins and natriuretic peptides has also been investigated (46, 47). More recently, exercise capacity and maximal oxygen consumption have emerged as potential biomarkers in cardio-oncology (48, 49).

Imaging surveillance in CSs allows the early identification of CTR-CVT, as also reported in the recent ESC guidelines (29). Among multiple cardiac imaging techniques used in patient surveillance, the most accessible is echocardiography, although cardiac magnetic resonance and coronary computed tomography may be as valuable as echocardiography in selected cases. The monitoring of myocardial function during the post-treatment phase relies on left ventricular ejection fraction evaluation whereas during oncologic treatment its evaluation should be coupled with assessments of more sensitive functional parameters (e.g., global longitudinal strain) (54). Besides an annual clinical evaluation, moderate risk patients should have an echocardiogram every 5 years and high/ very-high risk patients at 1, 3 and 5 years and then every 5 years thereafter except in patients with overt symptomatology (29). With its ability to assess cardiac structure and function and to provide myocardial tissue characterization, multi-parametric cardiac magnetic resonance has a preeminent role in the assessment of CVD in cardio-oncology (55). However, its role in CSs is limited although the use of non-contrast cardiac magnetic resonance protocols was shown to be of value in particular settings (55). Moreover, coronary computed tomography may be useful in CSs to evaluate ischemia or myocardial dysfunction (56) and to detect subclinical atherosclerosis, quantified using the coronary artery calcium score. This well-known imaging biomarker is an indicator of the extent of coronary calcification and has independent prognostic value. An advantage of coronary computed tomography is that it may allow adequate planning of structural interventions in patients with complex valve diseases, which are frequently responsible for heart failure in this population (56).

Prevention in cardio-oncology is based on the ABCDEF approach (57) addressing the seven factors of AHA Life's Simple 7 (58). In the cardio-oncology perspective, “A” stands for age (a known enhancer of CV risk), aspirin (a widely used drug in CVD), “awareness of risk” (a pivotal point in prevention) and alcohol intake, “B” stands for Blood Pressure and Body Mass index, “C” stands for cigarette use and cholesterol, “D” for diet, diabetes and dose of cancer therapy, “E” for exercise, estrogen/progesterone, echocardiography and other diagnostic tools, F for “formation of cardio-oncologic team”, family history and genetic factors. Psychological and sociological issues have been recently added as components of a healthy life (59) (Figure 1). “Awareness of risk” highlights the importance of an increased awareness of CTR-CVT, and “Formation of a cardio-oncology team” the need for a truly multidisciplinary approach to cancer patients. The same parameters for cardiovascular health applied to the general population serve as references for preventative, non-pharmacological interventions to reduce the CV risk in CSs. The 2022 ESC guidelines state that “dietary patterns with a high intake of vegetables/fruits and whole grains are associated with lower rates of mortality and cancer recurrence than is the case for diets with a high content of refined grains, processed and red meats, and high-fat dairy products” (29). Regular physical activity and exercise have a documented favorable impact on CVD (60) and on NP levels, including an “exercise-induced sacubitril-like effect” (61), whereas unhealthy diets, inactivity and obesity are associated with cancer recurrence risk and a shortened survival, as shown in breast cancer survivors (62, 63). Physical activity pre-diagnosis is important in reducing cancer-specific and all-cause mortality, even more so is physical activity post diagnosis (64, 65).

In the primary prevention of CVR-CVT, randomized clinical trials have shown a beneficial effect of beta-blockers/angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers, administered during anthracycline treatment with or without trastuzumab, on left ventricular function decline, but in all trials the patient population was small and heterogeneous so a general recommendation cannot be made (66–68). As a “universal” strategy of cardioprotection for all patients is so unfeasible, a careful triage is needed to deliver cardioprotective treatment only to high-risk patients (69) as indicated also by guidelines (29). Cardioprotective pharmacological treatment of CSs must aggressively address pre-existing CVRFs and cancer-therapy-induced derangements in cardiometabolic pathways and should be combined with non-pharmacological interventions (70). The intersection of poor adherence to the cardiac medications necessitated by cancer treatment, chemotherapy-induced metabolic derangements (e.g., weight gain) (71) and cancer-treatment-induced reductions in cardiorespiratory reserve exemplify the dangerous combination of “hits” that may translate into a clinical cardiac event (35).

A more specific strategy would imply a customized treatment targeted to the side effect of cancer therapy, e.g. a rigid control of hypertension in patients treated with drugs affecting blood pressure such as tyrosine kinase inhibitors and VEGF inhibitors; a lipid-lowering therapy in patients treated with hormone therapy for prostate and breast cancer that often induce dyslipidemia (72); optimal treatment of diabetes in patients treated with PEG-L-asparaginase, corticosteroid-containing regimens, targeted therapies causing derangement in molecular pathways involved in glucose homeostasis, immune checkpoint inhibitors inducing immune-related adverse events such as type 1 diabetes. On the other hand, a tumour-oriented strategy would imply an aggressive treatment of the shared risk factors between cancer and CVD (e.g. obesity in breast cancer).

Among the late effects of RT, fibrosis involving all cardiac structures is of special importance (83). Furthermore, many chemotherapeutic agents cause oxidative stress, increasing the risk of RT-induced heart disease (RIHD) (84). The damage is chronic and usually becomes clinically evident after several years, increasing steadily over time (85, 86). However, the incidence of clinically relevant RIHD does not increase linearly and does not reach a plateau (87). The risk of RIHD is proportional to the radiation burden to the whole heart and to individual structures and differs depending on the setting. The RT fields used in breast cancer involve mostly the left anterior descending coronary artery and the left or right ventricle (depending on the irradiated breast) (88, 89). Not surprisingly, the risk of clinically relevant heart disease is higher for patients with left breast RT and is represented by CAD (90, 91). As the irradiated heart often behaves like a denervated heart, CAD may be under-diagnosed because silent ischemia is more frequent than in the general population (92). In RT for lung cancer, the risk of cardiac damage is primarily influenced by the site of the tumor (upper vs. lower lobes) and the type of RT: the risk associated with left-sided tumors is higher with dose-intensified three-dimensional conformal RT + intensity-modulated RT but not with stereotactic body RT (93). For several reasons, the most critical population at risk of RT-induced heart disease consists of patients cured of mediastinal lymphoma. The young age at the time of treatment and the high rate of complete remission are associated with an extended survival of at least 40 years that increases the probability of late CTR-CVT. Moreover, up to the 1990s, RT was delivered with extended and mantle fields and at high doses. While new modes of RT delivery have since been developed, patients successfully treated before their implementation are now in their 50s and 60s and are at very high risk of cardiac damage (94, 95). The most common phenotype of RIHD is CAD involving the left coronary artery with ostial, main trunk or LAD lesions, or the right coronary artery at the proximal level (96–98). RT-induced valvular heart disease has a high fibrotic and calcific component, rapidly progresses to severe forms and mostly involves the aortic valve (99, 100). Acute pericarditis is relatively common during or shortly after chest RT. However, it may evolve toward a chronic constrictive or effusive-constrictive pericarditis. These patients have a worse outcome than those with other types of constrictive pericarditis (101, 102). Autonomic dysfunction leading to an increased resting heart rate, impaired heart rate variability, atrial fibrillation and atrio-ventricular block (103) are other phenotypes of RT-induced heart disease.

The need for a lifelong surveillance in CSs treated by chest RT is well recognized, including in the recently released ESC guidelines, which recommend an annual CV risk assessment that includes ECG, measurement of NP levels and an assessment of CVRFs, echocardiography in asymptomatic high-risk adult CSs starting 5 years after RT (delivered to a volume that included the heart) and every 5 years thereafter, and non-invasive screening for CAD every 5–10 years in asymptomatic patients who received 15 Gy of median heart dose, starting 5 years after radiation (29). Screening for CAD may consist of physical or pharmacological stress tests, CT scan with assessment of the calcium score, coronary CT, or even coronary angiography (104–106). Of these, the calcium score and coronary CT have been used in many studies (105, 106). The choice should be made according to the availability of each test and according to the needs of the patient.

The evolution of RIHD can be accelerated by the presence of CVRFs. Chest RT is an independent risk factor for CAD (107–109). To prevent the progression of cardiac damage, patients should be encouraged to maintain a healthy lifestyle (110–112). Statins should be prescribed to patients with even mild dyslipidemia (113) and ACEI may have favorable effects on RT-induced fibrosis, both in the heart and in the lungs (114). Inappropriate sinus tachycardia secondary to autonomic dysfunction can be treated with BB, non-dihydropyridine calcium channel blockers and, in the rather frequent case of a hypotensive patient, ivabradine (115). Surgical treatment of RIHD is often challenging. Because many patients with valvular heart disease have CAD and/or pericardial disease, any intervention in those with extensive calcifications, mediastinal fibrosis or pericardial adhesion (frequently observed after mediastinal RT) is more difficult, and the short- and long- term outcomes accordingly worse (116–118). A multidisciplinary approach is recommended to assess and define the surgical risk in CSs with severe valvular heart disease (29). Percutaneous interventions are preferred over surgery whenever possible, even if the clinical outcome is still worse in patients with RIHD than in those who did not receive RT (119–121).