Cardioprotection for 20 Years for Children With Cancer

Cardioprotection for 20 Years for Children With Cancer

Dexrazoxane (Totect, Zinecard) provides long-term cardioprotection for children treated with doxorubicin for cancer, and its co-administration with doxorubicin should be standard of care, say researchers in a report published published January 20 in the Journal of Clinical Oncology.

The study team investigated heart function in 195 subjects almost two decades after they received the anthracycline chemotherapy agent doxorubicin for either acute lymphoblastic leukemia, Hodgkin lymphoma, or osteosarcoma.

About half received dexrazoxane along with their doxorubicin.

“Among young adult-aged survivors of childhood cancer, dexrazoxane was associated with a cardioprotective effect nearly 20 years after initial anthracycline exposure,” concluded investigators, led by Eric Chow, MD, a pediatric oncologist at Seattle Children’s Hospital, Seattle, Washington.

“Oncology providers should consider administering dexrazoxane to children and adolescents” being treated with doxorubicin, particularly with cumulative doses of 250 mg/m2 or more or an equivalent amount of another anthracycline, they said.

Jonathan Friedberg, MD, editor-in-chief of JCO, was more blunt in his summary of the relevance of the study: “Dexrazoxane should be considered as a standard cardioprotectant” for higher-dose doxorubicin in pediatric cancer, he said.

Underused in Children

Despite recent progress in cancer therapeutics, doxorubicin and other anthracyclines remain cornerstones of pediatric cancer treatment. However, they come with a risk of late-onset cardiomyopathy that can approach 25% in some groups by the time survivors are 40 years old, and the risk has not declined appreciably in 50 years, the authors point out.

Outside of using lower, possibly subtherapeutic doses of anthracyclines, dexrazoxane is the only cardioprotective option available to children with cancer.

It is already approved in the United States to protect patients with breast cancer from heart failure when they are treated with 300 mg/m2 or more of doxorubicin.

Even so, “dexrazoxane use has been limited in children” in part because “evidence of long-term benefits was lacking,” the investigators said.

The team sought to correct the problem with their new study, a collaboration between the international Children’s Oncology Group and the Dana-Farber Cancer Institute’s Childhood Acute Lymphoblastic Leukemia Consortium.

The 195 pediatric cancer survivors, many of whom were in randomized trials of dexrazoxane when they were patients, underwent cardiac function testing 18.1 ± 2.7 years after they were first diagnosed with cancer.

The cumulative doxorubicin dose was 297 ± 91 mg/m2.

Among the 51% of survivors who had received it, dexrazoxane was administered in a 10:1 mg/m2 ratio to doxorubicin in an intravenous bolus before doxorubicin was administered.  

After adjusting for demographic characteristics, cumulative doxorubicin dose, and cardiac radiation exposure, the team found that dexrazoxane was associated with a reduced risk of poor left ventricular function in young adulthood (defined as fractional shortening < 30% or ejection fraction < 50%; odds ratio, 0.24) as well as a superior ejection fraction (absolute difference +1.6%) and less myocardial stress as determined by B-type natriuretic peptide levels (median -6.7 pg/mL).

The cardioprotective effect was seen primarily in subjects who had a cumulative doxorubicin dose of 250 mg/m2 or more.

Overall, patients “assigned to doxorubicin with dexrazoxane were significantly more likely to have preserved left ventricular function” almost 20 years later. The difference is likely to become more pronounced with time as “heart failure following treatment for childhood cancer has a long latency period,” the investigators said.

No Increase in Risk for Relapse

Besides lack of long-term data, pediatric oncologists have sometimes shied away from dexrazoxane out of concerns that it could increase the risk of cancer relapse. However, the investigators noted that in their previous work, they found no association between dexrazoxane and differences in overall survival or an increased risk of relapses or second cancers after a similarly long follow-up. 

Their previous work also showed that long-term serious cardiovascular outcomes occurred less frequently among children treated with dexrazoxane (5.6% vs 17.6%), including cardiomyopathy (4% vs 8%).

The work was funded by the National Institutes of Health, the St. Baldrick’s Foundation, and the Leukemia and Lymphoma Society. Chow reported research funding from Abbott. Investigators also included employees of Rocket Pharma and Arcus Biosciences/Covance.

J Clin Oncol. Published online January 20, 2023. Abstract

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. Alex is also an MIT Knight Science Journalism fellow. Email: [email protected]

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