Late-Onset Cardiotoxicity in Pediatric Cancer Survivors: Comparison of Regimens


Key Points

  • Compared with doxorubicin-related cardiomyopathy risk, risk with epirubicin was approximately equivalent and risk with daunorubicin was reduced.
  • Risk with mitoxantrone was approximately 10 times greater than that with doxorubicin.

In a study reported in JAMA Oncology, Feijen et al found that daunorubicin was associated with decreased cardiomyopathy risk vs doxorubicin among pediatric cancer survivors, with epirubicin being approximately isoequivalent to doxorubicin. Risk associated with the anthraquinone mitoxantrone was found to be substantially higher than that with doxorubicin.

As stated by the investigators, “Many 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.”

Study Details

The objective of the multicenter cohort pooled data study was to determine optimal dose equivalence ratios for late-onset cardiomyopathy between doxorubicin and other anthracyclines and mitoxantrone. The population consisted of 20,367 5-year cancer survivors in the Childhood Cancer Survivor Study treated from 1970 to 1999; 5,741 in the Dutch Childhood Oncology Group LATER study diagnosed between 1963 and 2001; and 2,315 in the St. Jude Lifetime study treated from 1962 to 2005. Cumulative doses of each anthracycline and mitoxantrone and chest radiotherapy exposure were obtained from medical records.

The primary outcome measure was severe, life-threatening, or fatal cardiomyopathy by 40 years of age.

Agent-specific Cox proportional hazards models for cardiomyopathy risk were adjusted for chest radiotherapy, age at cancer diagnosis, sex, and exposure to anthracyclines or to mitoxantrone. An agent-specific cardiomyopathy equivalence ratio, relative to doxorubicin, was estimated for each dose category as a ratio of the hazard ratios, with a weighted mean used to determined the agent-specific equivalence ratio across dose categories.

Risk of Cardiomyopathy

Among the 28,423 survivors, 9,330 received doxorubicin, 4,433 received daunorubicin, 342 received epirubicin, 241 received idarubicin, and 265 received mitoxantrone.

After median follow-up of 20.0 years from diagnosis, 399 cardiomyopathy cases were observed. Relative to doxorubicin, the equivalence ratios were 0.6 for daunorubicin, 0.8 for epirubicin, and 10.5 for mitoxantrone, with outcome data being too limited to provide idarubicin-specific estimates. Ratios derived from a continuous linear dose-response relationship were similar for daunorubicin (0.5) and epirubicin (0.8). The relationship between risk with mitoxantrone and doxorubicin appeared to be better characterized by a linear exponential model.

The investigators concluded, “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.”

Eric J. Chow, MD, MPH, of the Clinical Research Division, Fred Hutchinson Cancer Research Center, is the corresponding author for the JAMA Oncology article.

Disclosure: The study was funded by National Cancer Institute grants, American Lebanese-Syrian Associated Charities, Dutch Cancer Society, and European Union 7th Framework Programme for Research, Technological Development, and Demonstration. The study authors' full disclosures can be found at

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