In this study, we found variation in how pediatric patients treated with cardiotoxic chemotherapy were followed, both during treatment and post-exposure. Nearly 90% of survey respondents indicated cancer patients were screened prior to and during therapy, primarily with ECG and echocardiogram; only 12% reported evaluation by a cardiologist prior to therapy. According to the survey, only 20% of survivors were seen in a survivor clinic with cardiology involvement while 50% were seen in a survivor clinic without cardiology involvement. The data suggest an opportunity for cardiologists to partner with oncology teams at critical periods in disease management. We believe that a low threshold for early cardiology involvement in identifying and managing high risk patients may be considered. Even in this survey that is biased towards tertiary care centers with advanced HF therapies (63% respondents), our data suggests opportunity to improve survivorship care. Aside from addressing ventricular dysfunction, data from this study suggest an opportunity to increase efforts in cardiovascular risk factor management when seeing pediatric cancer survivors.
Developing standardized practice
We observed variability in the overall cardiac care delivery to this population. Potential reasons for the variability can range from provider knowledge, referral practices, tailored care for a diverse population with differing anti-cancer exposures, and/or the need for more standardized cardiology protocols in this new field. A number of best practice and consensus statements have been published regarding the diagnosis, prevention, and management of cardiovascular complications of cancer therapies in adults [3,4,5,6,7,8,9,10,11,12]. With the exception of adult survivors of childhood cancers, there is a dearth of evidence-based literature that can guide screening and management of cardiac disease in children and adolescents actively undergoing therapy and in those who survived cancer treatment but yet to have reached adulthood. In 1992, Steinherz and colleagues published the first imaging recommendations in children [13]. The COG published its first long-term survivor follow-up guidelines based on expert opinion in 2003, with serial updates every several years, providing specific follow-up recommendations based on age at chemotherapy treatment, thoracic radiation exposure, and cumulative anthracycline dose (www.survivorshipguidelines.org). The 2013 American Heart Association (AHA) Scientific Statement provides a detailed review of the literature on the subject, identifies areas of future research, and provides some guidance regarding evaluation and management of survivors of pediatric and adolescent cancers [14]. All these publications highlight the relative lack of and need for more evidence-based data to assist recommendations for monitoring, prevention, and treatment guidelines [14]. Additionally, the International Late Effects of Childhood Cancer Guideline Harmonization Group publication, a large meta-analysis of multiple international consensus based recommendations on the topic, highlighted the need for long-term follow-up studies assessing the efficacy of screening on outcome measures or cost effectiveness [15].
In the case of pediatric and adolescent patients, guidelines have been produced to address management of heart failure in general but are not specific to cardio-oncology [16]. While the COG does have guidance for following cancer survivors, there is a dearth of guidelines for monitoring patients during active cancer therapy, or after cardiac abnormalities develop. This gap in knowledge of how to manage a large proportion of pediatric cancer patients needs to be addressed. For example, while multiple clinical trials in adults have reported a benefit with ACE inhibitors [17], there are very few pediatric trials in cancer patients with mixed results. A recent trial that randomized 84 pediatric patients with leukemia to receive 6 months of ACE inhibitor did not show a difference in left ventricular systolic dysfunction between treatment and placebo groups; however, fewer patients in the treatment group showed an increase in pro-brain natriuretic peptide compared to the placebo group [18]. Moreover, some authors have raised concern that use of ACE inhibitors in pediatric patients could possibly exacerbate a unique pathologic remodeling pattern [19]. Fortunately, current multi-center studies are recruiting participants to better understand the development of cardiotoxicity during therapy and in survivors [20], and the utility of prophylactic medical therapy to prevent development of ventricular dysfunction [21].
The current survey showed a variety of tools being used to assess ventricular function (Table 1). Adult-based guidelines support the use of many of these methods, but stress the importance of using the same technique throughout care for a given patient [8]. While patients are being primarily followed by oncologists for their cancer care, the primary specialty responsible for the long-term medical sequelae of cancer therapy and maintenance of health remains to be defined [22]. In the future, the timely early inclusion of cardiovascular specialists into the care of patients with cancer may improve outcomes. Cardiologists can help optimize cardiac risk factor management and more importantly, the primary prevention of cardiovascular events. Collaboration of cardiologists and oncologists in clinical practice and also research will continue to make gains on the survival of childhood cancer patients. Further areas of research would include, but not be limited to: cardioprotective therapy, appropriate cost-effective screening tools; role of incorporation of advanced imaging techniques into surveillance, use of biomarkers, anticipatory guidance and preventive care; and appropriate therapeutic strategies from medical therapy to advanced cardiac support.
Prevention and education
A 2015 survey of Cardiology program directors predominately at adult centers, carried out by the ACC Cardio-oncology Section, found that > 70% felt that the implications of cancer treatment on cardiovascular health were an important consideration in patient care, and yet almost 40% of the participants did not feel confident in dealing with such issues or gave themselves an average rating when asked about their understanding of pertinent issues [23]. A more recent 2019 ACC survey of cardiology program directors showed that only 9% of programs had Cardio-oncology-specific training opportunities, and all of them require prior cardiology fellowship training [24]. Furthermore, there was “no formalized training for pediatric cardio-oncology” in the United States [23]. To improve the educational gaps in cardio-oncology for practicing physicians practice, “a number of live courses have been developed” over the last several years, and “there ..[has been] a greater number of cardio-oncology–focused sessions [included] at national meetings” [24]. However, the most effective way to disseminate standardized education and practice guidelines of cardio-oncology among new physicians is to incorporate it as part of Cardiology fellowship curriculum [25]. As being done in adult cardiology programs, systematic integration of cardio-oncology into fellowship training would likely improve the knowledge base, and practice among new pediatric cardiology physicians.
While there is an understanding of the importance of cardiovascular care for pediatric patients during and after cancer therapy, there is a lack of operationalized care and opportunities for improvement. In pediatric centers, care for the cardio-oncology patient often has resided in highly specialized heart failure clinics. However, studies consistently show that the cumulative burden of chronic cardiovascular conditions is substantial in childhood cancer survivors as they age, and there is a need to develop a more comprehensive, holistic and accessible approach to patient care [26]. The involvement of general cardiologists is vital to such an approach. Importantly, recent studies report that traditional risk factors such as hypertension, diabetes, obesity and smoking can further potentiate treatment-associated late effects [27, 28], and is an important point for medical intervention. For example, long-term HL survivors treated in childhood with radiation therapy had significantly higher risk of obstructive CAD and valve disease with higher blood pressures [26]. Involvement of general cardiologists and primary care providers, therefore, seems to be important in the cardiac care of this population as they grow and age.
Limitations and future directions
This study is limited in being a voluntary sample of selected individuals, i.e. those involved in the ACC Adult Congenital and Pediatric Cardiology Section. Another limitation is the lack of detailed demographics on respondents. Therefore, indications for imaging could not be assessed.
There is a need for more multi-institutional studies in pediatric cancer survivors along with research examining the specific mechanisms of late cardiovascular effects, for which little research exists. Biological studies are also important in formulating suitable interventions that may have longer lasting effects. Intervention studies such as methods of cardiovascular risk factor modification and use of cardioprotective agents to mitigate the risk of late effects are also vital.
