Letter by Lipshultz Regarding Article, “Anthracycline Cardiotoxicity: Worrisome Enough to Have You Quaking?”
2018; Lippincott Williams & Wilkins; Volume: 122; Issue: 7 Linguagem: Inglês
10.1161/circresaha.118.312918
ISSN1524-4571
Autores Tópico(s)Cancer-related cognitive impairment studies
ResumoHomeCirculation ResearchVol. 122, No. 7Letter by Lipshultz Regarding Article, "Anthracycline Cardiotoxicity: Worrisome Enough to Have You Quaking?" Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBLetter by Lipshultz Regarding Article, "Anthracycline Cardiotoxicity: Worrisome Enough to Have You Quaking?" Steven E. Lipshultz Steven E. LipshultzSteven E. Lipshultz Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI Originally published30 Mar 2018https://doi.org/10.1161/CIRCRESAHA.118.312918Circulation Research. 2018;122:e62–e63To the Editor:The important editorial by Bernstein1 in the January 19, 2018, issue of Circulation Research on preclinical models of anthracycline cardiotoxicity and cardioprotection, contains errors that should be corrected, lest they adversely affect clinical care.Dr Bernstein states that "Current prevention strategies involve limiting total exposure to anthracycline to the lowest possible dose and use of the iron chelator dexrazoxane. However, as a result of the potential for an increased risk of secondary malignancies, the European Medicines Agency has limited the indication for dexrazoxane to adult patients with advanced disease and contraindicated its use in children. Thus, the search for a more effective preventive therapeutic is critical, and the contribution of Gupta et al suggests a new pathway that is worth investigating."Dr Bernstein is of course correct in encouraging the use of preventive measures to reduce anthracycline-induced cardiotoxicity. Dexrazoxane provides substantial protection against anthracycline cardiotoxicity without reducing its oncological efficacy, even allowing safer anthracycline dose escalation.2,3 He is also correct in saying that dexrazoxane is approved for women with breast cancer. However, in 2014, the US Food and Drug Administration granted dexrazoxane pediatric orphan drug status,4 and dexrazoxane has never been contraindicated in the pediatric population in the United States.4 Further, in 2017, the European Medicines Agency (EMA) issued a decision that means that children expected to receive a cumulative dose of >300 mg/m2 of doxorubicin or the equivalent cumulative dose of another anthracycline are no longer contraindicated from treatment with dexrazoxane.5,6 This recent decision allows virtually all children to receive dexrazoxane starting with the first dose of anthracycline at the discretion of the treating provider.Specifically, in July 2017, the EMA concluded that dexrazoxane should not be contraindicated in children at the highest risk of cardiotoxicity.5,6 The EMA found no data indicating that dexrazoxane was associated with an increase in second primary malignancies, interfered with chemotherapy, or increased the risk for early death in children. The changes made by the EMA in July 2017 related to dexrazoxane as an approved cardio-oncology protectant.5,6 The label change for dexrazoxane followed a review by the EMA that, since 2016, has been posted and updated on the EMA website to help share the data and new updated label.5,6New data presented to the EMA in 2016 included the results of multicenter randomized clinical trials that were published in high-impact peer-reviewed journals.2,3 Alongside the amendment of the contraindication of dexrazoxane in children was a reassessment of its overall safety profile.5,6 In July 2017, the EMA approved a change in dexrazoxane labeling which could change clinical practice in the European Union.5,6Although dexrazoxane was given pediatric orphan drug status by the US Food and Drug Administration in 2014,4 it has been available for many years. For more than a decade, children in Brazil and other South and Central American countries have received dexrazoxane.7,8 Patients in Mexico have also received dexrazoxane.9,10 Similarly, for children in South Korea11,12 and Canada, dexrazoxane has been available for many years. Finally, although dexrazoxane was in fact unavailable for children in EMA countries between 2011 and 2017, this is no longer true.Dexrazoxane is also the most consistent anthracycline cardioprotective agent identified in animal models and confirmed in clinical studies.13 Although dexrazoxane markedly suppresses anthracycline cardiotoxicity, its cardioprotective activity is not complete, perhaps because anthracyclines have several potential cardiotoxic mechanisms.14,15 Dexrazoxane may interfere with some, but not all, of these mechanisms.I agree with Bernstein1 that animal models are needed to explore these potential cardiotoxic mechanisms14,15 and might help identify potential cardioprotective agents. To increase the likelihood of identifying such agents, preclinical studies searching for new cardioprotective agents should consider using procedures that can be reproduced in other experimental laboratories.13 Dr Bernstein and his colleagues have emphasized the importance of identifying an appropriate model of human anthracycline cardiotoxicity by stating, "This platform also holds considerable promise for the discovery of new doxorubicin-induced cardiotoxicity cardioprotectants, although our findings—that the iron-chelator dexrazoxane was not cardioprotective, whereas the antioxidant N-acetyl cysteine was—may highlight the differences between a whole-animal model and an in vitro isolated cardiomyocyte model."16 We have also emphasized the importance of preclinical models of anthracycline cardiotoxicity that reflect the clinical problem.13,17We have summarized some of the variables affecting the reproducibility of experimentally induced anthracycline cardiotoxicity.13,17 Further, preclinical studies of anthracycline cardiotoxicity would be of more clinical value if they incorporated a chronic component because the cardiac phenotype in children with anthracycline cardiomyopathy shifts from an early dilated cardiomyopathy to a later progressive restrictive cardiomyopathy.2,3,13 Preclinical models of anthracycline cardiotoxicity and cardioprotection should also incorporate multi-agent chemotherapeutic drug combinations to improve translational understanding.13 Multi-agent anthracycline cardioprotection against multi-agent chemotherapy should be tested in preclinical models with or against dexrazoxane to determine whether cardioprotection is incremental or improved, respectively.13 Validated cardiac biomarkers such as serum cardiac troponin-T and NT-proBNP (N-terminal pro-B-type natriuretic peptide) measurements as surrogate end points should be used in preclinical studies to assess the state of anthracycline cardiotoxicity.13,18 The use of preclinical models to assess genetic susceptibility for cardiotoxicity may also help to define high-risk groups and to characterize mechanisms of anthracycline cardiotoxicity and its prevention or reduction.13In conclusion, horizontally integrating preclinical and clinical studies of anthracyclines is important to improving and implementing cardioprotective strategies in patients at high risk for cardiovascular events with the aim to enhance their quality of life.Steven E. LipshultzDepartment of PediatricsWayne State University School of MedicineDetroit, MISources of FundingThis work was supported in part by grants from the National Institutes of Health (HL072705, HL078522, HL053392, CA127642, CA068484, HD052104, AI50274, CA 127642, CA068484, HD052102, HD052104, HL087708, HL079233, HL004537, HL087000, HL007188, HL094100, HL095127, HD80002), Pfizer, Roche Diagnostics, the Children's Cardiomyopathy Foundation, Sofia's Hope, Inc, the Kyle John Rymiszewski Foundation, the Children's Hospital of Michigan Foundation, the Scott Howard Fund, and the Michael Garil Fund.DisclosuresS.E. Lipshultz is a consultant for Clinigen.FootnotesLetters to the Editor will be published, if suitable, as space permits. They should not exceed 1000 words (typed double-spaced) in length and may be subject to editing or abridgment.References1. Bernstein D. Anthracycline cardiotoxicity: worrisome enough to have you quaking?Circ Res. 2018; 122:188–190. doi: 10.1161/CIRCRESAHA.117.312395.LinkGoogle Scholar2. Bansal N, Amdani S, Lipshultz ER, Lipshultz SE. Chemotherapy-induced cardiotoxicity in children.Expert Opin Drug Metab Toxicol. 2017; 13:817–832. doi: 10.1080/17425255.2017.1351547.CrossrefMedlineGoogle Scholar3. Lipshultz SE, Adams MJ, Colan SD, et al; American Heart Association Congenital Heart Defects Committee of the Council on Cardiovascular Disease in the Young; Council on Basic Cardiovascular Sciences; Council on Cardiovascular and Stroke Nursing, Council on Cardiovascular Radiology. Long-term cardiovascular toxicity in children, adolescents, and young adults who receive cancer therapy: pathophysiology, course, monitoring, management, prevention, and research directions: a scientific statement from the American Heart Association.Circulation. 2013; 128:1927–1995. doi: 10.1161/CIR.0b013e3182a88099.LinkGoogle Scholar4. Lipshultz SE, Franco VI, Sallan SE, Adamson PC, Steiner R, Swain SM, Gligorov J, Minotti G. Dexrazoxane for reducing anthracycline-related cardiotoxicity in children with cancer: an update of the evidence.Prog Pediatr Cardiol2014; 36:39–49.CrossrefGoogle Scholar5. European Medicines Authority. Outcome of a Procedure Under Article 13 of Regulation (EC) No 1234/2008.http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Cardioxane/human_referral_000421.jsp&mid=WC0b01ac05805c516f. Accessed 12 February, 2018.Google Scholar6. European Commission. Pharmaceuticals Community Register. Cardioxane Art 13.http://ec.europa.eu/health/documents/community-register/html/ho26321.htm. Accessed 12 February, 2018.Google Scholar7. de Matos Neto RP, Petrilli AS, Silva CM, Campos Filho O, Oporto VM, Gomes Lde F, Paiva MG, Carvalho AC, Moisés VA. Left ventricular systolic function assessed by echocardiography in children and adolescents with osteosarcoma treated with doxorubicin alone or in combination with dexrazoxane.Arq Bras Cardiol. 2006; 87:763–771.MedlineGoogle Scholar8. Paiva MG, Petrilli AS, Moisés VA, Macedo CR, Tanaka C, Campos O. Cardioprotective effect of dexrazoxane during treatment with doxorubicin: a study using low-dose dobutamine stress echocardiography.Pediatr Blood Cancer. 2005; 45:902–908. doi: 10.1002/pbc.20488.CrossrefMedlineGoogle Scholar9. Paladio-Hernández J, Martínez-Morales J. Cost-effectiveness of cardioprotective effect of dexrazoxane (Cardioxane®) in advanced/metastatic breast cancer patients treated with anthracycline-based chemotherapy in México.Value Health. 2015; 18:A454. doi: 10.1016/j.jval.2015.09.1154.CrossrefMedlineGoogle Scholar10. Sánchez-Medina J, Gonzalez-Ramella O, Gallegos-Castorena S. The effect of dexrazoxane for clinical and subclinical cardiotoxicity in children with acute myeloid leukemia.J Pediatr Hematol Oncol. 2010; 32:294–297. doi: 10.1097/MPH.0b013e3181d321b3.CrossrefMedlineGoogle Scholar11. Kang M, Kim KI, Song YC, Shin WG, Oh JM. Cardioprotective effect of early dexrazoxane use in anthracycline treated pediatric patients.J Chemother. 2012; 24:292–296. doi: 10.1179/1973947812Y.0000000038.CrossrefMedlineGoogle Scholar12. Choi HS, Park ES, Kang HJ, Shin HY, Noh CI, Yun YS, Ahn HS, Choi JY. Dexrazoxane for preventing anthracycline cardiotoxicity in children with solid tumors.J Korean Med Sci. 2010; 25:1336–1342. doi: 10.3346/jkms.2010.25.9.1336.CrossrefMedlineGoogle Scholar13. Lipshultz SE, Herman EH. Anthracycline cardiotoxicity: the importance of horizontally integrating pre-clinical and clinical research.Cardiovasc Res. 2018; 114:205–209. doi: 10.1093/cvr/cvx246.CrossrefMedlineGoogle Scholar14. Renu K, V G A, P B TP, Arunachalam S. Molecular mechanism of doxorubicin-induced cardiomyopathy - An update.Eur J Pharmacol. 2018; 818:241–253. doi: 10.1016/j.ejphar.2017.10.043.CrossrefMedlineGoogle Scholar15. Cappetta D, Rossi F, Piegari E, Quaini F, Berrino L, Urbanek K, et al. Doxorubicin targets multiple players: a new view of a new problem.Pharmacol Res2018; 127:4–14. doi: 10.1016/j.phrs.2017.03.016.CrossrefMedlineGoogle Scholar16. Burridge PW, Li YF, Matsa E, et al. Human induced pluripotent stem cell-derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity.Nat Med. 2016; 22:547–556. doi: 10.1038/nm.4087.CrossrefMedlineGoogle Scholar17. Lipshultz SE, Cohen H, Colan SD, Herman EH. The relevance of information generated by in vitro experimental models to clinical doxorubicin cardiotoxicity.Leuk Lymphoma. 2006; 47:1454–1458. doi: 10.1080/10428190600800231.CrossrefMedlineGoogle Scholar18. Lipshultz SE, Miller TL, Scully RE, et al. Changes in cardiac biomarkers during doxorubicin treatment of pediatric patients with high-risk acute lymphoblastic leukemia: associations with long-term echocardiographic outcomes.J Clin Oncol. 2012; 30:1042–1049. doi: 10.1200/JCO.2010.30.3404.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Rohani A (2021) Doxorubicin Induced Heart Failure with Reduced Ejection Fraction Clinical Cases in Cardio-Oncology, 10.1007/978-3-030-71155-9_6, (21-27), . Gándara-Mireles J, Lares-Asseff I, Reyes Espinoza E, Blanco J, González Font A, Córdova Hurtado L, Castañeda V, Fierro I, Romero L and Reyes H (2021) Association of genetic polymorphisms NCF4 rs1883112, CBR3 rs1056892, and ABCC1 rs3743527 with the cardiotoxic effects of doxorubicin in children with acute lymphoblastic leukemia, Pharmacogenetics and Genomics, 10.1097/FPC.0000000000000428, 31:5, (108-115), Online publication date: 1-Jul-2021. Bansal N, Blanco J, Sharma U, Pokharel S, Shisler S and Lipshultz S (2020) Cardiovascular diseases in survivors of childhood cancer, Cancer and Metastasis Reviews, 10.1007/s10555-020-09859-w, 39:1, (55-68), Online publication date: 1-Mar-2020. Bansal N, Adams M, Ganatra S, Colan S, Aggarwal S, Steiner R, Amdani S, Lipshultz E and Lipshultz S (2019) Strategies to prevent anthracycline-induced cardiotoxicity in cancer survivors, Cardio-Oncology, 10.1186/s40959-019-0054-5, 5:1, Online publication date: 1-Dec-2019. Bansal N, Amdani S, Hutchins K and Lipshultz S (2018) Cardiovascular disease in survivors of childhood cancer, Current Opinion in Pediatrics, 10.1097/MOP.0000000000000675, 30:5, (628-638), Online publication date: 1-Oct-2018. March 30, 2018Vol 122, Issue 7 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.118.312918PMID: 29599279 Originally publishedMarch 30, 2018 PDF download Advertisement SubjectsCardio-OncologyCardiomyopathyGene Expression and RegulationMyocardial Biology
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