Eighty percent of U.S. children diagnosed with cancer are living well into adulthood, resulting in nearly one in every 500 young adults in the U.S. achieving long-term cancer survivor status. These survivors are at persistent and progressively increased risk of cardiovascular-related complications, including an 8-fold increased risk of cardiac death and a 15-fold increased risk for experiencing heart failure in the first 30 years after cancer treatment compared to the general population.
“Although cardiac imaging techniques can assess heart structure and function, they lack the sensitivity needed to detect early treatment-induced cardiac injury and are not specific enough to indicate the persistent cardiotoxicity related to myocardial injury during therapy,” said Lipshultz, lead author of the study in the Journal of Clinical Oncology, posted online February 27, ahead of the print edition. “A comprehensive panel of biomarkers could be developed to assess cardiac status during therapy that is predictive of long-term outcome in these high-risk patients.”
The Miller School study suggests that a childhood cancer survivor with elevated cardiac biomarkers is more likely to have suffered persistent heart damage than a survivor with normal biomarkers, Lipshultz saidin. “Since tolerance of chemotherapy and predisposition to cardiac damage vary substantially among patients, this finding may lead the way to more effective, individualized patient care.”
The study, “Changes in Cardiac Biomarkers During Doxorubicin Treatment of Pediatric Patients With High-Risk Acute Lymphoblastic Leukemia: Associations With Long-Term Echocardiographic Outcomes,” was funded by the National Cancer Institute’s Office of Cancer Survivorship. In addition to Lipshultz, Miller School co-authors were Tracie L. Miller, M.D., professor of pediatrics and director of pediatric clinical research, Rebecca E. Scully, B.A., and Jacqueline M. Henkel, B.A., both research associates in pediatrics.
“Our results validated cardiac biomarkers of myocardial injury or cardiomyopathy that, when elevated during therapy, provided strong indications of who would have abnormal heart structure and function as measured by an abnormal echocardiogram five years later as a long-term cancer survivor,” said Lipshultz, who is also chief of staff at Holtz Children’s Hospital.
The study examined echocardiograms and serum measurements of several cardiac biomarkers in patients who participated in the Dana-Farber Cancer Institute Childhood ALL (acute lymphoblastic leukemia) Consortium Protocol 95-01, led by Stephen E. Sallan, M.D., at Dana-Farber, which enrolled patients younger than age 18 with newly diagnosed ALL between January 1996 and September 2000 throughout the United States, Canada and Puerto Rico.
Some patients in the study group were treated with doxorubicin, a chemotherapeutic agent known to have cardiotoxic effects. Because doxorubicin-induced cardiac damage is progressive and often irreversible, some patients in the study group also were given dexrazoxane to reduce cardiotoxicity.
The Miller team found increases in cardiac troponin T (cTnT) and cardiac troponin I (cTnI)—reflecting cardiac damage and often indicating irreversible death to heart muscle tissue—among patients who were treated with doxorubicin. Those patients also had chronic increases in N-terminal pro-brain natriuretic peptide (NT-proBNP), an indicator of increased left ventricular wall stress associated with pressure and volume overloads and increased diastolic pressure.
Increases in C-reactive protein (hsCRP) were also found, indicating cardiac stress, because of the role inflammation plays in heart disease. “The use of hsCRP as a biomarker to predict clinical cardiac events in children deserves particular attention because increased hsCRP levels are likely associated with worse cardiac characteristics,” Lipshultz said.
Researchers found that these key biomarkers were not elevated in children in the study group who also received the heart-protecting drug dexrazoxane. The percentage of patient samples with detectable cTnT remained stable, and the percentage of samples with increased NT-proBNP was consistently lower in the dexrazoxane-treated group throughout the course of treatment.
The study results also underscore the importance of dexrazoxane in reducing cardiotoxicity. “Measuring all these biomarkers during chemotherapy is also important, as it might help physicians to immediately identify cardiac injury and cardiomyopathy,” Lipshultz said.
He noted that the study also sets the stage for further assessments of biomarker-directed personalized therapy in the future.
“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,” Lipshultz said. “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.”
Other study co-authors included researchers from Harvard Medical School and a consortium of 10 other centers.