Research on the advances in radiation modeling presented by Rebecca M. Howell, PhD, at the 2023 American Society for Radiation Oncology (ASTRO) Annual Meeting may provide insights into the late cardiac effects of survivors of childhood cancer in the Childhood Cancer Survivor Study (CCSS).1 Dr. Howell is Professor of Radiation Physics at The University of Texas MD Anderson Cancer Center.
Complex Patterns
Dr. Howell presented results from a recently published report from the CCSS on the effects of whole heart and cardiac substructure radiation dose and the risk of late cardiac disease.2 The retrospective analysis included 25,481 survivors from the CCSS, among whom more than 12,000 were treated with radiation therapy. They individually considered heart failure, coronary artery disease, valve disease, and arrhythmia, as well as any cardiac disease.
Rebecca M. Howell, PhD
Uniquely, this study considered two different modeling approaches, excess relative rate models and piecewise exponential models to evaluate dose-response relationships. Excess relative rate modeling is commonly used by the radiation oncology community and considers radiotherapy effects to be additive, whereas piecewise exponential models are a standard approach in epidemiologic studies and consider radiotherapy effects to be multiplicative. Regardless of modeling approach, the researchers reported higher risks of cardiac diseases associated with higher mean whole heart and cardiac substructure doses, and that risk increased in a dose-dependent manner.
When the mean whole heart dose was evaluated with piecewise exponential models, an increased risk of cardiac disease was observed at doses greater than or equal to 10 Gy. Similarly, when mean substructure doses were evaluated, risk increased above 10 Gy. However, for some substructures and -specific cardiac outcomes, risk was elevated at lower doses of greater than or equal to 5 Gy (eg, risk of coronary artery disease was elevated at mean doses as low as 5 Gy to the right coronary artery and left ventricle). Additionally, excess relative rate modeling suggested that any dose to substructures may increase the risk of cardiac disease, with linear models being the best fit for most substructure endpoint dose-response relationships. In contrast, quadratic models were reported for most mean whole heart endpoints suggesting a dose threshold. Taken together both piecewise exponential and excess relative rate modeling flagged potential areas for consideration in cancer treatment planning (eg, lowering mean heart doses below 10 Gy and reducing cardiac substructure doses as much as possible without compromising target coverage). This report from the CCSS also shows that detailed radiation dosimetry can reveal complex patterns between radiation exposure and late cardiac disease risks.
“We’re filling the gap in knowledge about the exact dose-related risks in the cardiac system resulting from radiation therapy in childhood cancer survivors,” said Dr. Howell. “These findings highlight the need to practically apply these insights to refine treatment planning.”
Disparities in Cardiovascular Risk Factors in Childhood Cancer Survivors
Researchers also have identified a higher risk for hypertension, diabetes, and obesity in non-Hispanic Black and Hispanic survivors of childhood cancer compared with their non-Hispanic White counterparts, according to data published in JACC: CardioOncology.3
Findings from the CCSS revealed a higher incident rate ratio for hypertension of 1.4 among non-Hispanic Black cancer survivors. The cumulative incidence of diabetes, obesity, and multiple cardiovascular risk factors by the age of 40 was also notably higher among non-Hispanic Black and Hispanic cancer survivors.
“We found an increased vulnerability to cardiovascular diseases among survivors of childhood cancer, particularly among non-Hispanic Black and Hispanic cancer survivors,” noted lead study author David H. Noyd, MD, MPH, Pediatric Oncologist and Assistant Professor of Pediatrics at the University of Washington/Seattle Children’s Hospitals. “Recognizing these disparities is critical to provide targeted interventions and reduce the long-term health risks associated with childhood cancer survival.”
“We found an increased vulnerability to cardiovascular diseases among survivors of childhood cancer, particularly among non-Hispanic Black and Hispanic cancer survivors.”— David H. Noyd, MD, MPH
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Although the survival rates from childhood cancers have markedly improved over the past half century, authors of the study emphasized that cancer survivors are faced with an increased risk of long-term health issues, primarily from the cardiotoxic exposure from their cancer treatment. Studies have identified a higher incidence of serious cardiac events among these cancer survivors, particularly driven by treatments such as anthracyclines and chest irradiation.
Considering the inherent diabetes and obesity risk from the identified cardiotoxic treatments and the significant health inequities across racial and ethnic groups, Dr. Noyd said it is imperative to focus on early diagnosis and appropriate management of cardiovascular risk factors.
CCSS Design
The CCSS included 16,457 cancer survivors who were diagnosed at one of the North American centers between 1970 and 1999 and had survived at least 5 years after a diagnosis of leukemia or other malignancies. This retrospective cohort study used data from all available CCSS follow-up questionnaires from 2000 to 2017 to measure cardiovascular risk factors, including hypertension, hyperlipidemia, diabetes, and obesity.
Incidence of Hypertension, Diabetes, and Obesity
When cardiovascular disease risk factors were evaluated across the different racial and ethnic groups, non-Hispanic Black survivors reported a 1.4-fold higher incidence rate ratio for hypertension. Multivariate analysis also showed a higher cumulative incidence of diabetes among non-Hispanic Black and Hispanic cancer survivors by age 40 (8.4% and 9.7%, respectively; P < .001), compared with 5.1% of non-Hispanic White cancer survivors. Furthermore, nearly half of the non-Hispanic Black and Hispanic cancer survivors were found to be obese by age 40.
KEY POINTS
- Radiation dosimetry may reveal complex patterns between radiation exposure and late cardiac disease risks in childhood cancer survivors.
- Findings from the Childhood Cancer Survivor Study showed that non-Hispanic Black and Hispanic cancer survivors had a higher cumulative incidence of diabetes and obesity compared with non-Hispanic White cancer survivors.
- Additionally, non-Hispanic Black cancer survivors had a higher incidence of hypertension.
According to the study authors, the increased prevalence of cardiovascular risk factors among childhood cancer survivors from minority communities parallels the racial and ethnic disparities seen in the general population. However, they noted, these cardiovascular risk factors may potentially amplify the therapy-related cardiovascular risks associated with their survival, making their situation even more critical.
Study Limitations
The researchers noted several potential limitations of the CCSS. To begin, the findings rely on self-reported data from follow-up questionnaires, which may lead to inaccuracies. In addition, the childhood cancer survivor population was compared only with siblings and the general population, potentially leading to confounding by genetic, social, or environmental factors shared by cancer survivors and siblings. Finally, as this study was conducted in predominantly North American centers, its findings may not be representative of other populations around the world. More comprehensive research to include multiethnic and multinational representation is required for more accurate results, the authors noted.
“Prevention, early detection, and management of modifiable cardiovascular risk factors are essential to decrease cardiovascular disease burden,” Dr. Noyd concluded. “The unraveling of barriers to care, evidence-based interventions for cardiovascular risk factor control, and concerted efforts to dismantle structural racism are vital to reduce disparities in cardiovascular risk factors observed in the CCSS cohort, with the overarching goal to achieve health equity among all survivors of childhood cancer.”
DISCLOSURE: The Childhood Cancer Survivor Study was supported by grants from the National Cancer Institute. Dr. Howell and Dr. Noyd reported no conflicts of interest.
REFERENCES
1. Howell R: Advances in radiation dosimetry modeling to define the late cardiac effects of survivors of childhood cancer. 2023 ASTRO Annual Meeting. Abstract EDU 42. Presented October 4, 2023.
2. Bates JE, Shrestha S, Liu Q, et al: Cardiac substructure radiation dose and risk of late cardiac disease in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. J Clin Oncol 41:3826-3838, 2023.
3. Noyd DH, Liu Q, Yasui Y, et al: Cardiovascular risk factor disparities in adult survivors of childhood cancer compared with the general population. JACC CardioOncol 5:489-500, 2023.
