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Grant Details

Grant Number: 1R01CA211996-01 Interpret this number
Primary Investigator: Chow, Eric
Organization: Fred Hutchinson Cancer Research Center
Project Title: Dexrazoxane and Prevention of Anthracycline-Related Cardiomyopathy
Fiscal Year: 2017


Abstract

PROJECT SUMMARY Five-year survival among children with cancer now exceeds 80%. Late cardiovascular disease, including cancer therapy-related cardiomyopathy/heart failure (CHF), has now become the leading non-cancer cause of premature morbidity and mortality among childhood cancer survivors. Anthracycline and related drugs have been well-documented to be the single most important risk factor associated with subsequent development of CHF among cancer survivors. Anthracyclines, despite their known cardiotoxicity, continue to be an integral part of many contemporary pediatric cancer treatment protocols. Dexrazoxane (DRZ) is an EDTA-like bisdioxopiperazine that decreases oxygen free radicals via intracellular iron chelation, and is FDA-approved for use as a cardioprotectant in adults being treated with high-dose anthracyclines for breast cancer. The American Society of Clinical Oncology recommends considering its use for all adults exposed to high doses of anthracyclines. However, concerns regarding DRZ’s safety and efficacy have limited its use in children. Four national phase 3 clinical trials that featured upfront DRZ randomization were conducted among more than 1,200 children with leukemias and lymphomas from 1995-2001. Patients were treated with a range of anthracycline (specifically, doxorubicin) doses still commonly used today. While some short- and intermediate- term data up to 5-years from these trials suggest that DRZ-exposed children had less acute cardiotoxicity and pathologic left ventricular remodeling, longer term data are lacking. The proposed research will attempt to ascertain long-term cardiovascular health in this population of childhood cancer survivors now that 15-20 years have elapsed since cancer diagnosis. Specifically, we will leverage the study infrastructure we have developed within the Children’s Oncology Group (COG; a member of the NCI’s National Clinical Trials Network) in order to prospectively ascertain current cardiac function via echocardiography and overall cardiovascular health among at least 200 survivors. This sample size will allow us to definitively determine if survivors randomized to DRZ have decreased markers of CHF compared with those treated on the standard non-DRZ arms. We will then combine prospective echocardiographic data with archived data collected by the original clinical trialists and those available from participating COG institutions to examine whether DRZ exposure is associated with a differential trajectory of echocardiographic change over time. Finally, we will deploy a variety of approaches, including use of administrative and insurance databases, to capture long-term adverse health outcomes from almost the entire study population. We believe successful completion of the proposed research will allow us to determine whether DRZ provides long-term cardioprotection, with immediate clinical implications for current patients and drug regulatory policy.



Publications

Utility of apical four-chamber longitudinal strain in the assessment of childhood cancer survivors: A multicenter study.
Authors: Mosgrove M.J. , Sachdeva R. , Stratton K.L. , Armenian S.H. , Bhat A. , Leger K.J. , Yang C. , Leisenring W.M. , Meacham L.R. , Sadak K.T. , et al. .
Source: Echocardiography (mount Kisco, N.y.), 2024 Feb; 41(2), p. e15766.
PMID: 38340258
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Cardiac imaging and biomarkers for assessing myocardial fibrosis in children with hypertrophic cardiomyopathy.
Authors: Kirmani S. , Woodard P.K. , Shi L. , Hamza T.H. , Canter C.E. , Colan S.D. , Pahl E. , Towbin J.A. , Webber S.A. , Rossano J.W. , et al. .
Source: American Heart Journal, 2023 Oct; 264, p. 153-162.
EPub date: 2023-06-12 00:00:00.0.
PMID: 37315879
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RBL2 Regulates Cardiac Sensitivity to Anthracycline Chemotherapy.
Authors: Xia P. , Chen J. , Sapkota Y. , Scott E.N. , Liu Y. , Hudson M.M. , Rassekh S.R. , Carleton B.C. , Ross C.J.D. , Chow E.J. , et al. .
Source: Jacc. Cardiooncology, 2023 Jun; 5(3), p. 360-373.
EPub date: 2023-03-28 00:00:00.0.
PMID: 37397090
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Dexrazoxane and Long-Term Heart Function in Survivors of Childhood Cancer.
Authors: Chow E.J. , Aggarwal S. , Doody D.R. , Aplenc R. , Armenian S.H. , Baker K.S. , Bhatia S. , Blythe N. , Colan S.D. , Constine L.S. , et al. .
Source: Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology, 2023-01-20 00:00:00.0; , p. JCO2202423.
EPub date: 2023-01-20 00:00:00.0.
PMID: 36669148
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Mitigating, monitoring, and managing long-term chemotherapy- and radiation-induced cardiac toxicity.
Authors: Bottinor W. , Chow E.J. .
Source: Hematology. American Society Of Hematology. Education Program, 2022-12-09 00:00:00.0; 2022(1), p. 251-258.
PMID: 36485088
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Cardiometabolic Risk in Childhood Cancer Survivors: A Report from the Children's Oncology Group.
Authors: Lipshultz E.R. , Chow E.J. , Doody D.R. , Armenian S.H. , Asselin B.L. , Baker K.S. , Bhatia S. , Constine L.S. , Freyer D.R. , Kopp L.M. , et al. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2022-03-01 00:00:00.0; 31(3), p. 536-542.
PMID: 34810210
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The genetic architecture of pediatric cardiomyopathy.
Authors: Ware S.M. , Bhatnagar S. , Dexheimer P.J. , Wilkinson J.D. , Sridhar A. , Fan X. , Shen Y. , Tariq M. , Schubert J.A. , Colan S.D. , et al. .
Source: American Journal Of Human Genetics, 2022-02-03 00:00:00.0; 109(2), p. 282-298.
EPub date: 2022-01-12 00:00:00.0.
PMID: 35026164
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Late health outcomes after dexrazoxane treatment: A report from the Children's Oncology Group.
Authors: Chow E.J. , Aplenc R. , Vrooman L.M. , Doody D.R. , Huang Y.V. , Aggarwal S. , Armenian S.H. , Baker K.S. , Bhatia S. , Constine L.S. , et al. .
Source: Cancer, 2021-10-13 00:00:00.0; , .
EPub date: 2021-10-13 00:00:00.0.
PMID: 34644414
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Challenges associated with retrospective analysis of left ventricular function using clinical echocardiograms from a multicenter research study.
Authors: Sachdeva R. , Stratton K.L. , Cox D.E. , Armenian S.H. , Bhat A. , Border W.L. , Leger K.J. , Leisenring W.M. , Meacham L.R. , Sadak K.T. , et al. .
Source: Echocardiography (mount Kisco, N.y.), 2021-01-24 00:00:00.0; , .
EPub date: 2021-01-24 00:00:00.0.
PMID: 33486820
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Longitudinal Changes in Echocardiographic Parameters of Cardiac Function in Pediatric Cancer Survivors.
Authors: Border W.L. , Sachdeva R. , Stratton K.L. , Armenian S.H. , Bhat A. , Cox D.E. , Leger K.J. , Leisenring W.M. , Meacham L.R. , Sadak K.T. , et al. .
Source: Jacc. Cardiooncology, 2020 Mar; 2(1), p. 26-37.
EPub date: 2020-03-17 00:00:00.0.
PMID: 32719829
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The Evolving Design of NIH-Funded Cardio-Oncology Studies to Address Cancer Treatment-Related Cardiovascular Toxicity.
Authors: Minasian L. , Dimond E. , Davis M. , Adhikari B. , Fagerstrom R. , Fabian C. , Floyd J. , Unger J.M. , Douglas P.S. , Mustian K.M. , et al. .
Source: Jacc. Cardiooncology, 2019 Sep; 1(1), p. 105-113.
EPub date: 2019-09-24 00:00:00.0.
PMID: 32529192
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Traditional cardiovascular risk factors and individual prediction of cardiovascular events in childhood cancer survivors.
Authors: Chen Y. , Chow E.J. , Oeffinger K.C. , Border W.L. , Leisenring W.M. , Meacham L.R. , Mulrooney D.A. , Sklar C.A. , Stovall M. , Robison L.L. , et al. .
Source: Journal Of The National Cancer Institute, 2019-06-04 00:00:00.0; , .
EPub date: 2019-06-04 00:00:00.0.
PMID: 31161223
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Paediatric cardio-oncology: epidemiology, screening, prevention, and treatment.
Authors: Chow E.J. , Leger K.J. , Bhatt N.S. , Mulrooney D.A. , Ross C.J. , Aggarwal S. , Bansal N. , Ehrhardt M.J. , Armenian S.H. , Scott J.M. , et al. .
Source: Cardiovascular Research, 2019-04-15 00:00:00.0; 115(5), p. 922-934.
PMID: 30768157
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Derivation of Anthracycline and Anthraquinone Equivalence Ratios to Doxorubicin for Late-Onset Cardiotoxicity.
Authors: Feijen E.A.M. , Leisenring W.M. , Stratton K.L. , Ness K.K. , van der Pal H.J.H. , van Dalen E.C. , Armstrong G.T. , Aune G.J. , Green D.M. , Hudson M.M. , et al. .
Source: Jama Oncology, 2019-01-31 00:00:00.0; , .
EPub date: 2019-01-31 00:00:00.0.
PMID: 30703192
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