There are an estimated 500,000 childhood cancer survivors in the United States, a number that will increase exponentially in the coming years. Over half of all childhood cancer survivors will have received cardiotoxic therapies during primary cancer treatment or relapse. For these survivors, there is a well-established association between cumulative anthracycline and/or chest radiation dose and cardiovascular disease, including heart failure. Typically, there is a variable period of asymptomatic cardiac dysfunction that precedes clinically overt heart failure, which can be identified through cardiac imaging such as echocardiography. For many survivors of childhood cancer, cardiac dysfunction will not become clinically apparent until years after completion of therapy. This latency to disease onset raises concern for potential loss to follow-up, delayed recognition of adverse health events, and subsequently poorer outcomes once it is clinically evident.
Anticipation of potential cancer treatment–related late effects by providers is essential to allow timely interventions to prevent or decrease the burden of cardiovascular complications and improve quality of life. As such, there has been a growing interest in identifying novel screening modalities (eg, cardiac imaging or blood biomarkers) for asymptomatic disease and in determining the optimal surveillance frequency in survivors who are expected to live decades beyond their cancer diagnosis.
Saro Armenian, DO, MPH
In 2015, the International Guideline Harmonization Group (IGHG) developed evidence-based recommendations for risk stratification (low, intermediate, high) according to anthracycline and/or chest radiation dose exposures.1 Lifelong echocardiographic screening was recommended for all at-risk survivors, but the frequency (minimum of every 5 years) was based on consensus, due to a paucity of longitudinal data on the trajectory of change in cardiac function. That said, in the medical community, there has been a growing awareness about the adverse effects of intensive lifelong screening related to the potential for greater harms and higher costs. This awareness has led to a “value-based” view of the tradeoffs among the benefits, harms, and costs of different screening strategies.2
High-value screening strategies provide a benefit that justifies the harms and associated costs, whereas low-value strategies result in disproportionately few health benefits relative to the harms and costs incurred. Value and intensity are not the same. More intensive screening may provide greater benefit in lives extended than less intensive strategies, but it also often leads to increased harms and costs. Intensification of screening strategies often results in higher false-positive results, diagnostic workups, and costs, which may not be justified by the incremental increase in benefit. Optimizing value requires finding the intermediate level of intensity that best balances benefits on the one hand with harms and costs on the other.
Assessment of Different Screening Strategies
There are challenges to conducting research to inform value-based screening in childhood cancer survivors, given the long disease latency of many late effects and the large numbers needed to detect a significant effect. To address these challenges, researchers have utilized simulation modeling to evaluate the clinical effectiveness and cost-effectiveness of different screening strategies.
Most recently, investigators determined that lifelong screening for cardiac dysfunction was not cost-effective for survivors deemed to be at low risk per the IGHG guidelines—a population that represents nearly 40% of survivors for whom screening is currently recommended.3 The recently reported study by Leerink et al,4 reviewed in this issue of The ASCO Post, provides much-needed objective data to further refine the IGHG screening recommendations.
Using a longitudinal cohort design, they identified important prognostic clinical and echocardiographic parameters to differentiate survivors who will develop cardiac dysfunction from those for whom the risk is negligible (10-year probability ≤ 3%). The strengths of this article include its large sample size, careful phenotyping of echocardiographic data, thoughtful risk prediction model building, and external validation of their findings. Of note, their combined clinical plus echocardiogram-based risk prediction model was able to categorize nearly 75% of survivors as very low risk for cardiac dysfunction, a population for whom lifelong screening may not be necessary. These findings have the potential to be practice changing and speak to the commitment of the childhood cancer survivorship research community to challenge conventional clinical care.
The findings of Leerink et al should be considered in the context of the current landscape of childhood cancer survivorship care. All study participants had an initial screening echocardiogram at a median of 17 years from their cancer diagnosis and a follow-up echocardiogram at a median of 11 years thereafter, likely representing a highly engaged long-term survivor population. Estimates from the North America–based cohorts are that less than 40% of long-term childhood cancer survivors undergo routine risk-based echocardiographic screening, with the lowest screening rates among survivors who are farthest from their cancer diagnosis. As such, implementation of echocardiogram-based risk prediction may be especially challenging for the large proportion of survivors who may not be as engaged in survivorship-focused care.
Nevertheless, the model developed by Leerink et al represents an important platform for others to build on, either through the addition of modifiable risk factors (eg, physical inactivity, diabetes, hypertension) or germline genetic risk scores. The development of more sophisticated models will require collaborative international efforts with larger numbers of survivors. The pediatric oncology community long ago recognized the power of collaboration, and this will no doubt be the impetus for our continued efforts to improve the well-being of the growing population of long-term survivors.
Dr. Armenian is Director of the Childhood Cancer Survivorship Program at the City of Hope Comprehensive Cancer Center, California.
Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO or The ASCO Post.
DISCLOSURE: Dr. Armenian reported no conflicts of interest.
1. Armenian SH, Hudson MM, Mulder RL, et al: Recommendations for cardiomyopathy surveillance for survivors of childhood cancer: A report from the International Late Effects of Childhood Cancer Guideline Harmonization Group. Lancet Oncol 16:e123-e136, 2015.
2. Harris RP, Wilt TJ, Qaseem A: A value framework for cancer screening: Advice for high-value care from the American College of Physicians. Ann Intern Med 162:712-717, 2015.
3. Ehrhardt MJ, Ward ZJ, Liu Q, et al: Cost-effectiveness of the International Late Effects of Childhood Cancer Guideline Harmonization Group Screening Guidelines to prevent heart failure in survivors of childhood cancer. J Clin Oncol 38:3851-3862, 2020.
4. Leerink JM, van der Pal HJH, Kremer LCM, et al: Refining the 10-year prediction of left ventricular systolic dysfunction in long-term survivors of childhood cancer. J Am Coll Cardiol CardioOnc 3:62-72, 2021.
In a Dutch study reported in JACC: CardioOncology, Jan M. Leerink, PhD candidate, of Amsterdam UMC, University of Amsterdam Department of Clinical and Experimental Cardiology, and colleagues found that the addition of ejection fraction measurement at the time of first surveillance echocardiogram...