Chemotherapy differences in long-term cardiomyopathy risk in children

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An analysis of long-term cardiomyopathy risk in 28,000 childhood cancer survivors in the US and Europe, researchers compared four chemotherapy drugs with development of cardiomyopathy and found exposure to different anthracyclines results in different long-term cardiovascular risk.

In long-term survivors of childhood cancer, cardiovascular disease is a leading cause of early death from non-cancer causes. In a study, researchers compared four chemotherapy drugs with development of cardiomyopathy (abnormal heart muscle with impaired function) years after treatment.

“Exposure to anthracycline chemotherapies, such as doxorubicin, has long been associated with an increased risk of cardiovascular disease in long-term childhood cancer survivors,” said Dr Gregory Aune, of UT Health San Antonio. “Previously, it was assumed that exposure to any member of the anthracycline class carried the same risk of late cardiovascular complications. By studying the outcomes of over 28,000 long-term survivors in the US 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.”

The drug daunorubicin was associated with decreased cardiomyopathy risk when compared to doxorubicin, the study showed. Mitoxantrone, another chemotherapy, appeared 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 Dr Gail Tomlinson, professor of paediatrics, division director of paediatric haematology-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 minimising late effects.”

Aune, assistant professor of paediatric hematology-oncology at UT Health San Antonio and an investigator with the university’s Greehey Children’s Cancer Research Institute, assisted in the study design and review. Co-authors are from the Netherlands; the Fred Hutchinson Cancer Research Centre in Seattle; St Jude Children’s Research Hospital in Memphis; the Duke University School of Medicine; and the University of Washington-Seattle.

Abstract
Importance: 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.
Objective: To determine optimal dose equivalence ratios for late-onset cardiomyopathy between doxorubicin and other anthracyclines or the anthraquinone mitoxantrone.
Design, Setting, and Participants: This multicenter cohort study of childhood cancer survivors who survived 5 or more years analyzed data pooled from 20 367 participants in the Childhood Cancer Survivor Study treated from 1970 to 1999, 5741 participants in the Dutch Childhood Oncology Group LATER study diagnosed between 1963 and 2001, and 2315 participants in the St Jude Lifetime study treated from 1962 to 2005.
Exposures: Cumulative doses of each agent (the anthracyclines doxorubicin, daunorubicin, epirubicin, and idarubicin; and the anthraquinone mitoxantrone) along with chest radiotherapy exposure were abstracted from medical records.
Main Outcomes and Measures: 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 estimated 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.
Results: Of 28 423 survivors (46.4% female; median age at cancer diagnosis 6.1 years [range, 0.0-22.7 years]), 9330 patients received doxorubicin, 4433 received daunorubicin, 342 received epirubicin, 241 received idarubicin, and 265 received mitoxantrone. After a median follow-up of 20.0 years (range, 5.0-40.0 years) following receipt of a cancer diagnosis, 399 cardiomyopathy cases were observed. Relative to doxorubicin, the equivalence ratios were 0.6 (95% CI, 0.4-1.0) for daunorubicin, 0.8 (95% CI, 0.5-2.8) for epirubicin, and 10.5 (95% CI, 6.2-19.1) for mitoxantrone. Outcomes were too rare to generate idarubicin-specific estimates. Ratios based on a continuous linear dose-response relationship were similar for daunorubicin (0.5 [95% CI, 0.4-0.7]) and epirubicin (0.8 [95% CI, 0.3-1.4]). The relationship between mitoxantrone and doxorubicin appeared better characterized by a linear exponential model.
Conclusions and Relevance: 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.

Authors
Elizabeth AM Feijen, Wendy M Leisenring, Kayla L Stratton, Kirsten K Ness, Helena JH van der Pal, Elvira C van Dalen, Gregory T Armstrong, Gregory J Aune, Daniel M Green, Melissa M Hudson, Jacqueline Loonen, Kevin C Oeffinger, Leslie L Robison, Yutaka Yasui, Leontien CM Kremer, Eric J Chow

University of Texas Health Science Centre San Antonio material
JAMA Oncology abstract


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