Biomarkers expose child cancer treatment heart risk
Doxorubicin is used to treat acute lymphoblastic leukemia (ALL) in children. ALL is a cancer of the blood that can kill within a few weeks if left untreated. But this drug that can save lives also has a darker side--it can damage the heart irreversibly, and according to a team of researchers from the University of Miami, tracking certain heart biomarkers could give physicians a heads-up as to which children are at high risk.
The researchers, from the Miller School of Medicine, treated children with ALL with either doxorubicin or doxorubicin with dexrazoxane, a drug that protects the heart, and looked at three biomarkers of heart damage. The markers, cardiac troponin T (cTnT), a cardiac injury biomarker; N-terminal pro-brain natriuretic peptide (NT-proBNP), a cardiomyopathy biomarker); and high-sensitivity C-reactive protein (hsCRP), an inflammatory and heart stress biomarker, were measured before, during and after treatment.
They found that levels of cTnT and NT-proBNP were increased in children receiving doxorubicin alone compared with those who also received the heart protectant drug. These increased levels suggest heart damage or even heart muscle death. The biomarker increases were also linked with changes in the thickness of the heart wall four years later, which suggests longer-term damage and increased risk of later heart problems. The children receiving doxorubicin also had increased levels of hsCRP, which is linked with worse cardiac characteristics. The research is published in the Journal of Clinical Oncology.
"While definitive validation studies are required to fully establish their range of clinical utility, our study showed that cTnT and NT-proBNP may hold promise as biomarkers of cardiotoxicity in children with high-risk ALL," said Dr. Steven E. Lipshultz, professor and chair of pediatrics. "Ideally, this will help physicians in the future as they strive to maximize oncologic efficacy, minimize cardiotoxicity and help long-term survivors achieve the highest possible quality of life."
Monitoring and protecting heart health in survivors of childhood cancer is vital, as 80% of those diagnosed with cancer as children in the U.S. now live into adulthood, and in the 30 years after treatment, children who survive cancer have an eightfold increased chance of cardiac death and a fifteenfold increased risk of heart failure. Further validation is needed, but these biomarkers could help physicians monitor and treat early signs of heart damage, and support researchers in developing less heart-toxic chemotherapy regimens based on existing and new drugs.
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--- Journal of Clinical Oncology article ---
Changes in Cardiac Biomarkers During Doxorubicin Treatment of Pediatric Patients With High-Risk Acute Lymphoblastic Leukemia: Associations With Long-Term Echocardiographic Outcomes ©American Society of Clinical Oncology
Abstract
Purpose Doxorubicin causes cardiac injury and cardiomyopathy in children with acute lymphoblastic leukemia (ALL). Measuring biomarkers during therapy might help individualize treatment by immediately identifying cardiac injury and cardiomyopathy.
Patients and Methods Children with high-risk ALL were randomly assigned to receive doxorubicin alone (n = 100; 75 analyzed) or doxorubicin with dexrazoxane (n = 105; 81 analyzed). Echocardiograms and serial serum measurements of cardiac troponin T (cTnT; cardiac injury biomarker), N-terminal pro-brain natriuretic peptide (NT-proBNP; cardiomyopathy biomarker), and high-sensitivity C-reactive protein (hsCRP; inflammatory biomarker) were obtained before, during, and after treatment.
Results cTnT levels were increased in 12% of children in the doxorubicin group and in 13% of the doxorubicin-dexrazoxane group before treatment but in 47% and 13%, respectively, after treatment (P = .005). NT-proBNP levels were increased in 89% of children in the doxorubicin group and in 92% of children in the doxorubicin-dexrazoxane group before treatment but in only 48% and 20%, respectively, after treatment (P = .07). The percentage of children with increased hsCRP levels did not differ between groups at any time. In the first 90 days of treatment, detectable increases in cTnT were associated with abnormally reduced left ventricular (LV) mass and LV end-diastolic posterior wall thickness 4 years later (P < .01); increases in NT-proBNP were related to an abnormal LV thickness-to-dimension ratio, suggesting LV remodeling, 4 years later (P = .01). Increases in hsCRP were not associated with any echocardiographic variables.
Conclusion cTnT and NT-proBNP may hold promise as biomarkers of cardiotoxicity in children with high-risk ALL. Definitive validation studies are required to fully establish their range of clinical utility.
Received May 7, 2010. Accepted December 20, 2011. |
