Anthracyclines are part of many effective pediatric cancer treatment protocols. Most pediatric oncology treatment groups assume that the hematologic toxicity of anthracycline agents is equivalent to their cardiotoxicity; for example, Children’s Oncology Group substitution rules consider daunorubicin; and epirubicin isoequivalent to doxorubicin, whereas mitoxantrone and idarubicin are considered 4 to 5 times as toxic as doxorubicin.
In long-term survivors of childhood cancer, cardiovascular disease is a leading cause of early death from non-cancer causes. In a new study, published Jan. 31 in JAMA Oncology; researchers compared four chemotherapy drugs with development of cardiomyopathy (abnormal heart muscle with impaired function) years after treatment.

Cardiomyopathy equivalence ratio

Cardiomyopathy (severe, life-threatening, or fatal) by 40 years of age. Agent-specific Cox proportional hazards models evaluated cardiomyopathy risk, adjusting for chest radiotherapy, age at cancer diagnosis, sex; and exposure to anthracyclines or to an anthraquinone. An agent-specific cardiomyopathy equivalence ratio (relative to doxorubicin); was estimating for each dose category as a ratio of the hazard ratios; and then a weighted mean determined the overall agent-specific equivalence ratio across all dose categories.

“Exposure to anthracycline chemotherapies, such as doxorubicin; has long been associating with an increased risk of cardiovascular disease; in long-term childhood cancer survivors,” said Gregory Aune, M.D., Ph.D.; of UT Health San Antonio. “Previously, it was assuming that exposure to any member of the anthracycline class; and carried the same risk of late cardiovascular complications.

By studying the outcomes of over 28,000 long-term survivors in the U.S. and Europe, this research indicates that exposure to different anthracyclines results in variable long-term cardiovascular risk. In the future, it will be important to take these differences into account when screening long-term survivors for cardiovascular complications and in the development of modern treatment regimens.”

Cardiovascular risk

The drug daunorubicin was associating with decreased cardiomyopathy risk; when compared to doxorubicin, the study show. Mitoxantrone, another chemotherapy, appearing to have greater long-term cardiomyopathy risk than was previously estimated.
“The past several decades have been focused on devising combinations of drugs that work best for curing patients,” said Gail Tomlinson, M.D., Ph.D., professor of pediatrics, division director of pediatric hematology-oncology, and holder of the Greehey Distinguished Chair in Genetics and Cancer at UT Health San Antonio. “This has been a highly successful process with a substantial increase in survival for most cancer types. Now with so many survivors alive many years from their original cancer, it is imperative to fine-tune protocols based on the goal of minimizing late effects.”
In a large data set assembled to examine long-term cardiomyopathy risk in childhood cancer survivors, daunorubicin was associated with decreased cardiomyopathy risk vs doxorubicin, whereas epirubicin was approximately isoequivalent. By contrast, the current hematologic-based doxorubicin dose equivalency of mitoxantrone (4:1) appeared to significantly underestimate the association of mitoxantrone with long-term cardiomyopathy risk.