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Original Investigation
January 31, 2019

Derivation of Anthracycline and Anthraquinone Equivalence Ratios to Doxorubicin for Late-Onset Cardiotoxicity

Author Affiliations
  • 1Department of Pediatric Oncology, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
  • 2Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
  • 3Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
  • 4Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
  • 5Department of Epidemiology and Cancer Control, St Jude Children’s Research Hospital, Memphis, Tennessee
  • 6Department of Pediatrics, Greehey Children’s Cancer Research Institute, The University of Texas Health Science Center at San Antonio
  • 7Department of Oncology, St Jude Children’s Research Hospital, Memphis, Tennessee
  • 8Department of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands
  • 9Department of Medicine, Duke University School of Medicine, Durham, North Carolina
  • 10Department of Pediatrics, Seattle Children’s Hospital, University of Washington, Seattle
JAMA Oncol. Published online January 31, 2019. doi:10.1001/jamaoncol.2018.6634
Key Points

Question  Can evidence-based equivalence ratios for late-onset cardiomyopathy be determined between doxorubicin and other anthracyclines or an anthraquinone agent among childhood cancer survivors?

Findings  This large cohort study of 28 423 childhood cancer survivors with detailed cancer treatment exposures found that compared with doxorubicin, the anthraquinone mitoxantrone was associated with more cardiotoxic risk than current guidelines would suggest, whereas the anthracycline daunorubicin was associated with less cardiotoxic risk. The anthracycline epirubicin appeared isoequivalent to doxorubicin.

Meaning  The cardiotoxicity equivalence ratios determined in the present study for the most commonly used cancer treatment agents may influence the choice of agents when designing new protocols.

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.

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