More than half of the 380,000 long-term childhood cancer survivors in the United States face significantly increased risk for anthracycline induced cardiac morbidity and mortality. Despite the known cardiotoxic effects of these drugs [1], 50 % of the 12,400 children (<20 years) diagnosed with cancer each year receive anthracyclines as an essential component of their treatment protocols [2, 3]. The occurrence of cardiotoxicity is directly associated with the cumulative dose of anthracycline and increases over time [4–11], with morphological changes on myocardial biopsy noted in virtually all patients treated with doses of >240 mg/m² [4]. Exposure to 250 mg/m² or more of anthracyclines increases the relative hazard of congestive heart failure (CHF) 2–5 times, when compared to unexposed long-term survivors and has a five-fold increase in cardiovascular related mortality when compared to the general population [12].

Overall childhood cancer survivors experience 11 times the number of expected deaths than the general population [13]. Although the standardized mortality rate (SMR) declines with increase in follow-up and attained age, significant excess mortality persists in this patient population. The purpose of this study was to investigate the impact of anthracycline induced myocardial dysfunction, as defined by a SF < 29 %, on late onset cardiomyopathy and overall mortality in childhood cancer survivors. In addition, we sought to identify subpopulations of subjects at the highest risk for cardiomyopathy and death from all causes.

This study was approved by the Connecticut Children’s Medical Center Institutional Review Board. All subjects were identified through a registry of pediatric cancer patients treated with anthracyclines between 1985 and 2013. The registry provides retrospective data regarding medical and cardiac history, chemotherapy, stem cell and radiation therapy, retrospective and prospective cardiac imaging and serologic biomarkers from pediatric cancer patients treated at CCMC. Subjects met inclusion criteria if they had a pediatric cancer diagnosis, received anthracyclines as part of their chemotherapy; and were ≤ 21 years at time of diagnosis. These subjects are followed at Connecticut Children’s Medical Center with yearly physical examinations and periodic echocardiograms based on age at treatment, radiation dose and cumulative anthracycline dose [14]. The medical records of all enrolled subjects were reviewed to identify known risk factors associated with cardiotoxicity, including cumulative anthracycline dose, length of post-therapy interval, administration of other potentially cardiotoxic medications (vinca alkaloids), pre-existing heart disease, radiation dose to the heart, bone marrow transplant, age at diagnosis, gender, systolic dysfunction, and history of congestive heart failure during anthracycline therapy. For analytic purposes, specific chemotherapeutic agents were grouped into anthracycline chemotherapeutic agents and vinca alkaloids [15]. We used the following formulas to convert to doxorubicin isotoxic equivalents prior to calculating total cumulative anthracycline dose: doxorubicin: total dose × 1; daunorubicin: total dose × 0.833; idarubicin: total dose × 5; mitoxantrone: total dose × 4 [14].

Subjects’ values from medical record review and TTE were combined in a single study database. Group differences were compared using t-tests or their non parametric analogues for continuously distributed variables, chi-square and exact tests were utilized for categorical variables such as gender and previous SF < 29 %. Univariate logistic regression was used to select statistically significant risk factors for cardiotoxicity against the outcomes of SF < 29 % and all-cause mortality. These statistically significant risk factors became covariates in the multiple logistic regression model for each outcome. Kaplan-Meier survival analysis was used to demonstrate the effect of previous myocardial dysfunction on survival. All tests were two-tailed, and p < 0.05 was considered to indicate a statistically significant difference. SPSS software (IBM, Armonk, New York) was used for statistical analysis.

Our findings indicate that long term pediatric cancer survivors with evidence of anthracycline induced myocardial dysfunction, defined as a history of SF <29 %, experienced a seven fold increase in risk of death. In addition, subjects with a history of SF <29 % had a cumulative survival of 54 % at 25 years, compared to 85 %, in the group with no previous myocardial involvement. Other factors, including increased length of post chemotherapy interval, younger age of diagnosis, total cumulative anthracycline dose, history of BMT and a solid tumor diagnosis, were also associated with increased risk for all-cause mortality. The association between myocardial dysfunction and all cause mortality including cancer related deaths is a novel finding in this patient population and brings attention to the adverse cumulative effect of comorbidities among patients living with chronic diseases. The effect of comorbidity on adverse outcomes has been previously described in patients with cancer and heart failure. The risk of cancer and non cardiovascular related mortality was found to be higher in heart failure (HF) compared with HF-free subjects by Hasin et al. [17]. Furthermore, the presence of overt cardiomyopathy may limit the options for additional chemotherapy with anthracyclines or with protocols containing cardiotoxic agents such as the use of biologic targeted therapies (e.g., sorafenib), a common exclusion criteria on clinical trials. Further studies will be needed to examine the mechanisms of this association.

The increased risk of cardiomyopathy among survivors of childhood cancer, who already experience significant excess mortality, underscores the importance of surveillance for subclinical myocardial dysfunction in this patient population. Recent consensus guidelines by the American Society of Echocardiography (ASE) and the European Association of Cardiovascular Imaging (EACVI) advocate the use of standard transthoracic echocardiographic techniques in addition to 2D strain and 3D imaging acquisition for the diagnosis of Cancer Therapeutics–Related Cardiac Dysfunction (CTRCD) in adult patients during and after cancer therapy. In addition, cardiac magnetic resonance imaging is emerging as an important technique for detection of subclinical and overt cardiotoxicity given its excellent reproducibility for assessment of left ventricular volume, mass and function and unique capability for tissue characterization of the left and right ventricular myocardium [18–21]. Several serum biologic soluble markers including N-terminal pro-BNP (NT-pro-BNP), cardiac troponin T (cTnT) and cardiac troponin I (cTnI) have been found to be useful markers in the early detection of AIC [22, 23]. Implementation of a multimodality imaging approach including the use of serologic biomarkers to best identify subclinical myocardial dysfunction, may allow clinicians to detect structural myocardial abnormalities prior to the development of heart failure. Furthermore, given the inherent differences between pediatric and adult patients exposed to anthracycline therapy, guidelines for multimodality imaging in children for routine surveillance of patients should be established.

The period of subclinical cardiotoxicity is characterized by structural and functional myocardial abnormalities and is highly prevalent amongst asymptomatic pediatric cancer survivors [21, 24–28]. Treatment of subclinical dysfunction with Enalapril and possibly Carvedilol may help prevent or decrease the incidence of cardiac events if started earlier after chemotherapy [29, 30] and in addition may decrease cancer progression and cancer specific mortality in some patients [31]. Furthermore, the use of dexrazoxane is able to reduce cardiac injury associated with the use of doxorubicin [22, 32]. Future studies designed to assess the effect of early implementation of these therapeutic strategies on all cause mortality may help clarify this important question.

Consistent with previous studies, preexisting heart disease, age at diagnosis, cumulative anthracycline dose, and bone marrow transplant were significant risk factors associated with myocardial dysfunction [33, 34]. Persistent cardiomyopathy occurred in 22 % of subjects with previous myocardial dysfunction, and in agreement to previous reports, was associated with a survival of < 50 % at 5 years [35]. Previous heart disease, radiation to the chest and BMT were significant risk factors associated with persistent cardiomyopathy [12].

Our specific cause of mortality is similar to that observed in the Childhood Cancer Survivor Study (CCSS) [36], and the British Childhood Cancer Survivor Study [13]. Recurrence of cancer was the most common cause of death, followed by treatment-related consequences and secondary or subsequent cancers. In a large cohort of childhood cancer survivors, the risk of dying as a result of cardiac disease was significantly higher in individuals who received a cumulative anthracycline dose of greater than 360 mg/m² and who received radiation dose that exceeded 5Gy [12]. In addition, our findings indicate that anthracycline induced myocardial dysfunction increases the risk of death from all causes as well as the risk of dying as a result of cardiac disease.

We have assembled an interdisciplinary team of cardiologists, and oncologists to implement primary secondary and tertiary heart failure prevention strategies in childhood cancer survivors exposed to cardiotoxic chemotherapy [37]. With the goal of reducing the variability in clinical practice and improving outcomes, our team has developed a management tool in which the different interventions by each sub-specialist involved in the patient’s care is defined, optimized, and mapped out over time. The creation of this interdisciplinary team has facilitated the implementation of prevention strategies and development of clinical pathways of therapy designed to standardize clinical care among multiple subspecialists caring for these patients.

Our study demonstrates that patients with myocardial dysfunction, defined by a SF < 29 % at any time during or after anthracycline therapy had a lower cumulative survival. Through the interdisciplinary collaborations between cardiology and oncology, and development of evidence-based guidelines, geared towards early detection and treatment of subclinical cardiotoxicity clinicians may improve overall survival in this vulnerable population.