Although more than 85% of childhood cancer survivors will achieve a 5-year survival,1 that does not tell the whole tale for these individuals who move into adulthood. They are at excess risk of late mortality, even 40 years out from a cancer diagnosis, from non–cancer-related causes,1 and related modifiable lifestyle and cardiovascular risk factors require attention and possibly intervention. At the recent 2024 American College of Cardiology (ACC) course on Advancing the Cardiovascular Care of the Oncology Patient,2 Stephanie Dixon, MD, MPH, of the Division of Cancer Survivorship, Departments of Oncology and Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Memphis, explored strategies for mitigating the risks for cardiotoxicity in these cancer survivors through prevention or early identification.
Stephanie Dixon, MD, MPH
Late Cardiac Effects of Cancer Treatments
Chronic health conditions, such as cardiovascular disease, will often be the cause of mortality in these survivors—not the primary cancer.3 In addition, modifiable risk factors, such as smoking, alcohol use, physical activity, diabetes status/glucose control, and dyslipidemia, may also play a role in the future cardiovascular health of these patients. In some cases, these conditions are associated with the cancer treatments themselves. In addition, childhood cancer survivors are four times more likely to die of cardiac causes compared with the general population.3 Dr. Dixon and colleagues also reported that decades after a cancer diagnosis, stroke, ischemic heart disease, valvular heart disease, and heart failure were the largest noncancer contributors to excess deaths in this patient population.
Furthermore, the latency period from cancer treatment exposure seems to vary for treatment-related chronic conditions. Bhatia and colleagues found that generally, radiation-related late effects have a longer latency period than other treatments.4 The risk may be augmented by the dose of radiotherapy, patient age at exposure, genetics, and comorbid conditions, noted Dr. Dixon. “We know radiation exposure increases the risk of coronary artery disease,” she said.
However, Dr. Dixon continued, “it is not just chest-directed radiation.” The fields and delivery mechanisms of radiotherapy have improved with more focal treatments such as intensity-modulated radiation therapy and proton therapy. In a study presented in the Journal of Clinical Oncology,5 investigators found that low to moderate doses of radiation (5.0–19.9 Gy) to large cardiac volumes (≥ 50% of the heart) were linked to an increased rate of coronary artery disease (relative risk = 2.3).
In addition, Dr. Dixon said, cardiac substructure dosimetry—left anterior descending artery, left main coronary artery, left circumflex artery, right coronary artery, aorta, atrium, and ventricles—is important, too.5 “Even at relatively low doses of exposure (5–10 Gy), there is about a twofold increase in the risk of future coronary artery disease; and as the radiation dose increases, so does the risk,” she explained. Even at low doses, there is a fivefold increase in risk for valvular heart disease.5
Even at relatively low doses of exposure (5–10 Gy), there is about a twofold increase in the risk of future coronary artery disease; and as the radiation dose increases, so does the risk.— Stephanie Dixon, MD, MPH
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As for chemotherapy, “the effects can sometimes occur quite early with anthracycline-related cardiotoxicity,” Dr. Dixon noted, “but others may develop heart failure later in life, years or decades are their anthracycline chemotherapy exposure.” In fact, she added, exposure to anthracyclines above 250 mg/m2 increased the future risk of heart failure significantly. “Although we are using a number of targeted agents now, most of our pediatric patients treated for cancer are still seeing a lot of conventional chemotherapy, including anthracyclines,” commented Dr. Dixon.
Cardiovascular Disease Prevention Strategies
Dr. Dixon presented several case studies to explore the role of different types of cardiovascular disease prevention in adult survivors of childhood cancer. The intent of primordial prevention is to eliminate causative risk factors by providing risk-adapted therapy (eg, eliminating radiotherapy whenever possible). As for primary prevention, the goal is to mitigate causative risk factors; for example, risk-adapted therapy might include decreasing the dose of anthracyclines or other agents, identifying prediabetes, and preventing its progression. The intent of secondary prevention is to identify cardiac issues via screening echocardiograms or biomarkers, for instance, for asymptomatic left ventricular dysfunction.
• Case 1: Primordial Prevention: An 18-year-old female was treated with a combination chemotherapy regimen for newly diagnosed, stage IIIB bulky mediastinal Hodgkin lymphoma. “One of the main ways that primordial prevention has been done in childhood cancer—and Hodgkin lymphoma is a great example—is risk-adapted radiotherapy in minimizing exposures; so, we change from very large, extensive fields to smaller fields, by going from mantle radiation therapy (at 36 Gy) to involved-field or involved-node radiation (< 30 Gy),” explained Dr. Dixon. And, more recently, the use of proton therapy has become another primordial strategy for these younger patients. For some patients who have had an excellent response to systemic agents, radiation therapy may be avoided altogether.
“There is a very high burden of cardiovascular disease in long-term survivors of Hodgkin lymphoma,” Dr. Dixon. According to a study by Oeffinger et al,6 among nearly 3,000 survivors of childhood Hodgkin lymphoma, at a median age of 35, elimination of chest-directed radiation therapy was linked to a 70% reduction in cardiopulmonary disease when compared with extended-field, high-dose radiation.
Dr. Dixon also emphasized the importance of considering cumulative exposures to radiation and agents such as doxorubicin and cardiomyopathy risk. “The dose of anthracycline ≥ 250 mg/m2 and the likelihood and dose of radiation therapy very significantly impact cardiomyopathy risk,” she said.
• Case 2: Primary Prevention: A 20-year-old male with a history of heart transplant for viral myocarditis has not responded to treatment with rituximab alone for posttransplant lymphoproliferative disorder. Treatment with an anthracycline-containing regimen is being planned next.
Dr. Dixon noted that coadministration of the cardioprotective agent dexrazoxane is supported by the literature in such a case. Early data from childhood acute lymphoblastic leukemia and lymphoblastic lymphoma suggest the short-term cardioprotective effects of this agent include reductions in elevated troponin T after receipt of doxorubicin and improved measures of left ventricular remodeling and subclinical cardiomyopathy among those given doxorubicin.
In regard to the effects of dexrazoxane on heart function, Dr. Dixon said the best data to support long-term cardioprotection in pediatric patients with cancer comes from a recent study by Chow et al.7 “Among young adult–aged survivors of childhood cancer, dexrazoxane was associated with a cardioprotective effect nearly 20 years after initial anthracycline exposure,” the investigators concluded. Dexrazoxane was found to reduce myocardial wall stress and decrease the risk of ejection fraction less than 50% (specific to those given ≥ 250 mg/m2 of anthracycline).
Based on the findings of a systematic review,8 the International Guideline Harmonization Group (IGHG) proposed recommendations on the use of dexrazoxane in this setting. The benefits probably outweigh the possible risk of subsequent neoplasms, the IGHG notes, when the cumulative anthracycline dose is ≥ 250 mg/m2, but no recommendation can be made for use in those given less than this dose.
• Case 3: Secondary Prevention: A 25-year-old male had received both doxorubicin (250 mg/m2) and mediastinal radiation (21 Gy) for treatment of Hodgkin lymphoma. Dr. Dixon raised the question of how often this patient should undergo screening echocardiography for cardiomyopathy.
Those at high risk of cardiomyopathy [based on the doses of anthracycline and chest therapy received] should undergo screening echocardiography every 2 years.— Stephanie Dixon, MD, MPH
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Based on the IGHG screening recommendations for cardiomyopathy in such patients,9 those at high risk—having received an anthracycline at ≥ 250 mg/m2, chest radiation therapy ≥ 30 Gy, or both an anthracycline at ≥ 100 mg/m2 and chest radiation therapy ≥ 15 Gy—should undergo screening echocardiography every 2 years. For those at moderate risk—having received 100 to < 250 mg/m2 of an anthracycline or up to 15 to < 30 Gy of chest radiation—are advised to undergo screening echocardiography every 5 years. No such screening for cardiomyopathy is recommended for those at low risk (having received < 100 mg/m2 of an anthracycline or ≤ 15 Gy of chest radiation). Dr. Dixon shared another source of long-term follow-up guidelines for these patients, often used in North America, from the Children’s Oncology Group (survivorshipguidelines.org). Both sources align in terms of frequency of echocardiographic screening and dose cutpoints, she noted.
In closing, Dr. Dixon briefly mentioned the role of cardiac biomarkers—such as NT-proBNP (N-terminal prohormone of brain natriuretic peptide) and troponin T—in refining screening in adult survivors of childhood cancer. Although individually these markers were not adequate to identify cardiomyopathy, she noted, abnormal NT-proBNP has been associated with cardiotoxic therapy exposure in a dose-dependent manner. In addition, among survivors with normal left ventricular ejection fraction, abnormal NT-proBNP may be associated with future cardiomyopathy,10 particularly when global longitudinal strain is also abnormal.
DISCLOSURE: Dr. Dixon reported no conflicts of interest.
REFERENCES
1. Dixon SB, Liu Q, Chow EJ, et al: Specific causes of excess late mortality and association with modifiable risk factors among survivors of childhood cancer: A report from the Childhood Cancer Survivor Study cohort. Lancet 401:1447-1457, 2023.
2. Dixon S: Surviving and thriving: Promoting CV health in adult survivors of childhood cancers. 2024 ACC Conference: Advancing the Cardiovascular Care of the Oncology Patient. Presented February 10, 2024.
3. Ehrhardt MJ, Liu Q, Dixon SB, et al: Association of modifiable health conditions and social determinants of health with late mortality in survivors of childhood cancer. JAMA Netw Open 6:e2255395, 2023.
4. Bhatia S, Tonorezos ES, Landier W: Clinical care for people who survive childhood cancer: A review. JAMA 330:1175-1186, 2023.
5. Bates JE, Howell RM, Liu Q, et al: Therapy-related cardiac risk in childhood cancer survivors: An analysis of the Childhood Cancer Survivor Study. J Clin Oncol 37:1090-1101, 2019.
6. Oeffinger KC, Stratton KL, Hudson MM, et al: Impact of risk-adapted therapy for pediatric Hodgkin lymphoma on risk of long-term morbidity: A report from the Childhood Cancer Survivor Study. J Clin Oncol 39:2266-2275, 2021.
7. Chow EJ, Aggarwal S, Doody DR, et al: Dexrazoxane and long-term heart function in survivors of childhood cancer. J Clin Oncol 41:2248-2257, 2023.
8. de Baat EC, van Dalen EC, Mulder RL, et al: Primary cardioprotection with dexrazoxane in patients with childhood cancer who are expected to receive anthracyclines: Recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group. Lancet Child Adolesc Health 6:885-894, 2022.
9. Ehrhardt MJ, Leerink JM, Mulder RL, et al: Systematic review and updated recommendations for cardiomyopathy surveillance for survivors of childhood, adolescent, and young adult cancer from the International Late Effects of Childhood Cancer Guideline Harmonization Group. Lancet Oncol 24:e108-e120, 2023.
10. Ehrhardt MJ, Liu Q, Mulrooney DA, et al: Improved cardiomyopathy risk prediction using global longitudinal strain and N-terminal-pro-B-type natriuretic peptide in survivors of childhood cancer exposed to cardiotoxic therapy. J Clin Oncol. January 11, 2024 (early release online).
