The survival rate for childhood cancer has greatly improved over the past decades and is today above 80%. As a result, the cohort of adult childhood cancer survivors is steadily growing (1–3). Correspondingly, the risk of long term-side effects of cancer treatment including debilitating and sometimes fatal conditions is high, with a cumulative incidence of about 40 % after 30 years of follow-up (4). The most common forms of late complications and causes of death among childhood cancer survivors include secondary malignancies, cardiovascular diseases and pulmonary disorders (5, 6). Reports from the US Childhood Cancer Survivor Study has reported up to seven times higher risk of premature death due to cardiac complications among childhood cancer survivors as compared to the general population (5, 6). A wide variation of heart diseases in childhood cancer survivors have been reported (7–10). The most common cardiac condition in this population is heart failure, which has earlier been reported in a wide range with up to 15-fold higher risk compared to young people from the general population (4, 7, 11, 12).
According to the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) guidelines for the management of heart failure (HF) from 2013, HF is largely a clinical diagnosis based on a careful history and physical examination and cannot be characterized by a single diagnostic test. The cardinal clinical manifestations of HF are dyspnea, fatigue and fluid retention (13). The severity of HF was initially defined by the New York Heart Association (NYHA) functional classification, in which patients are assigned to one of four groups based on how much they are limited during physical activity (Table 1) (14). In addition, ACCF/AHA have developed a classification including four stages that complements the NYHA system (Table 2) (13). Both classifications provide useful information about the presence and severity of HF and have valuable prognostic implications. ACCF and AHA have defined HF as a complex clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood (13). Accordingly, the European Society of Cardiology (ESC) state HF as a clinical syndrome, characterized by typical symptoms (e.g. breathlessness, ankle swelling and fatigue) that may be accompanied by clinical signs (e.g. elevated jugular venous pressure, pulmonary crackles and peripheral oedema) caused by a structural and/or functional cardiac abnormality (15)
Table 1
NYHA functional classification
| Classification | Definition |
| I | No limitation of physical activity. Ordinary physical activity does not cause symptoms of HF. |
| II | Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in symptoms of HF. |
| III | Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes symptoms of HF. |
| IV | Unable to carry on any physical activity without symptoms of HF, or symptoms of HF at rest. |
| NYHA, New York Heart Association; HF, heart failure. |
Table 2
ACCF/AHA stages of heart failure.
| Stage | Definition |
| A | At high risk for HF but without structural heart disease or symptoms of HF. |
| B | Structural heart disease but without signs or symptoms of HF. |
| C | Structural heart disease with prior or current symptoms of HF. |
| D | Refractory HF requiring specialized interventions. |
| ACCF, American College of Cardiology Foundation; AHA, American Heart Association; HF, heart failure. |
Previous echocardiography investigations in childhood cancer survivors, who did not experience any symptoms, have reported a variety of structural and/or functional cardiac abnormalities, referred to as subclinical cardiotoxicity. Still, the observed frequency of such echocardiographic aberrations is highly inconsistent, and ranges from 0 % to 57% (16). There is no general consensus on how to define or classify subclinical cardiotoxicity (16, 17), which may, in part, explain the differences between previous studies. Furthermore, it is unclear to what degree subclinical cardiotoxicity in childhood cancer survivors may evolve into overt heart failure over time (16, 18).
Treatment with anthracyclines (ACs) has greatly improved survival rates in in children with cancer (19). A drawback is that the ACs are cardiotoxic and the risk for developing heart failure increases in parallel with the cumulative dose of these chemotherapeutics (8, 16, 20, 21). A dose of anthracyclines below 250 mg/m2 has been report to be associated with at low risk for cardiotoxicity, but for susceptible persons no dose is safe and individual risk factors including demographic features and comorbidities need to be considered as well (11, 21–23). The relative risk for heart failure due to different types of anthracyclines is arbitrary and mainly based on the assumption that hematological toxicity and cardiotoxicity are correlated (24). Published data on what doses of different ACs are safe with respect to cardiotoxicity and risk for subsequent heart failure are contradictory (25). Other types of chemotherapeutic drugs that have been seen to contribute to the cardiotoxic effect of ACs include tyrosine kinase inhibitors, alkylating agents and cisplatin (9). Radiation of the chest is also a risk factor for heart failure after treatment of childhood cancer and may also contribute to coronary artery disease and valvular heart disease (8, 26, 27). The highest risk for heart failure development is seen in survivors that have been treated with both anthracyclines and radiotherapy (8).
Patients treated for childhood cancers during the 1990s have shown a lower incidence of late cardiac complications, as compared to previous eras, particularly for coronary artery disease. This is probably due to modifications of treatment protocols, which include reductions in cardiotoxic chemotherapeutics and less cardiac radiation (10, 28). A report from the Dutch Childhood Oncology Group–Long-Term Effects After Childhood Cancer (DCOG-LATER) study 2019 showed decreased mortality due to heart failure when recent treatment periods were compared with older ones, but, somewhat paradoxically, an increase in the incidence of heart failure in more modern eras (26).
A synthesis of population-based studies reporting on the frequency of heart failure after childhood cancer treatment and examining whether the incidence and prevalence of this condition is changing over time is important. Not least, since the acquisition of such epidemiological knowledge is likely to be of value when generating future treatment protocols for childhood cancer and organizing post-treatment cardiac surveillance programs.