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

Elizabeth A.M. Feijen, Wendy M. Leisenring, Kayla L. Stratton, Kirsten K. Ness, Helena J.H. Van Der Pal, Elvira C. Van Dalen, Gregory Armstrong, Gregory J. Aune, Daniel M. Green, Melissa M. Hudson, Jacqueline Loonen, Kevin C. Oeffinger, Leslie L. Robison, Yutaka Yasui, Leontien C.M. Kremer, Eric J. Chow

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 20367 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 28423 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..

Original languageEnglish (US)
Pages (from-to)864-871
Number of pages8
JournalJAMA Oncology
Volume5
Issue number6
DOIs
StatePublished - Jun 1 2019

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Anthraquinones
Anthracyclines
Mitoxantrone
Doxorubicin
Cardiomyopathies
Epirubicin
Daunorubicin
Idarubicin
Survivors
Neoplasms
Antineoplastic Protocols
Radiotherapy
Thorax
Cardiotoxicity
Pediatrics
Poisons
Proportional Hazards Models
Multicenter Studies
Medical Records
Linear Models

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Feijen, E. A. M., Leisenring, W. M., Stratton, K. L., Ness, K. K., Van Der Pal, H. J. H., Van Dalen, E. C., ... Chow, E. J. (2019). Derivation of Anthracycline and Anthraquinone Equivalence Ratios to Doxorubicin for Late-Onset Cardiotoxicity. JAMA Oncology, 5(6), 864-871. https://doi.org/10.1001/jamaoncol.2018.6634

Derivation of Anthracycline and Anthraquinone Equivalence Ratios to Doxorubicin for Late-Onset Cardiotoxicity. / Feijen, Elizabeth A.M.; Leisenring, Wendy M.; Stratton, Kayla L.; Ness, Kirsten K.; Van Der Pal, Helena J.H.; Van Dalen, Elvira C.; Armstrong, Gregory; Aune, Gregory J.; Green, Daniel M.; Hudson, Melissa M.; Loonen, Jacqueline; Oeffinger, Kevin C.; Robison, Leslie L.; Yasui, Yutaka; Kremer, Leontien C.M.; Chow, Eric J.

In: JAMA Oncology, Vol. 5, No. 6, 01.06.2019, p. 864-871.

Research output: Contribution to journalArticle

Feijen, EAM, Leisenring, WM, Stratton, KL, Ness, KK, Van Der Pal, HJH, Van Dalen, EC, Armstrong, G, Aune, GJ, Green, DM, Hudson, MM, Loonen, J, Oeffinger, KC, Robison, LL, Yasui, Y, Kremer, LCM & Chow, EJ 2019, 'Derivation of Anthracycline and Anthraquinone Equivalence Ratios to Doxorubicin for Late-Onset Cardiotoxicity', JAMA Oncology, vol. 5, no. 6, pp. 864-871. https://doi.org/10.1001/jamaoncol.2018.6634
Feijen EAM, Leisenring WM, Stratton KL, Ness KK, Van Der Pal HJH, Van Dalen EC et al. Derivation of Anthracycline and Anthraquinone Equivalence Ratios to Doxorubicin for Late-Onset Cardiotoxicity. JAMA Oncology. 2019 Jun 1;5(6):864-871. https://doi.org/10.1001/jamaoncol.2018.6634
Feijen, Elizabeth A.M. ; Leisenring, Wendy M. ; Stratton, Kayla L. ; Ness, Kirsten K. ; Van Der Pal, Helena J.H. ; Van Dalen, Elvira C. ; Armstrong, Gregory ; Aune, Gregory J. ; Green, Daniel M. ; Hudson, Melissa M. ; Loonen, Jacqueline ; Oeffinger, Kevin C. ; Robison, Leslie L. ; Yasui, Yutaka ; Kremer, Leontien C.M. ; Chow, Eric J. / Derivation of Anthracycline and Anthraquinone Equivalence Ratios to Doxorubicin for Late-Onset Cardiotoxicity. In: JAMA Oncology. 2019 ; Vol. 5, No. 6. pp. 864-871.
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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 20367 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 28423 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..",
author = "Feijen, {Elizabeth A.M.} and Leisenring, {Wendy M.} and Stratton, {Kayla L.} and Ness, {Kirsten K.} and {Van Der Pal}, {Helena J.H.} and {Van Dalen}, {Elvira C.} and Gregory Armstrong and Aune, {Gregory J.} and Green, {Daniel M.} and Hudson, {Melissa M.} and Jacqueline Loonen and Oeffinger, {Kevin C.} and Robison, {Leslie L.} and Yutaka Yasui and Kremer, {Leontien C.M.} and Chow, {Eric J.}",
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TY - JOUR

T1 - Derivation of Anthracycline and Anthraquinone Equivalence Ratios to Doxorubicin for Late-Onset Cardiotoxicity

AU - Feijen, Elizabeth A.M.

AU - Leisenring, Wendy M.

AU - Stratton, Kayla L.

AU - Ness, Kirsten K.

AU - Van Der Pal, Helena J.H.

AU - Van Dalen, Elvira C.

AU - Armstrong, Gregory

AU - Aune, Gregory J.

AU - Green, Daniel M.

AU - Hudson, Melissa M.

AU - Loonen, Jacqueline

AU - Oeffinger, Kevin C.

AU - Robison, Leslie L.

AU - Yasui, Yutaka

AU - Kremer, Leontien C.M.

AU - Chow, Eric J.

PY - 2019/6/1

Y1 - 2019/6/1

N2 - 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 20367 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 28423 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..

AB - 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 20367 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 28423 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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