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A Doxorubicin-induced Cardiomyopathy Model in Adult Zebrafish
Published on: June 7, 2018
Longitudinal Change in Cardiac Function After Doxorubicin and Dexrazoxane: A Report From Children's Oncology Group
Erin M Mobley1, David R Doody2, Steven D Colan3
1Department of Surgery, College of Medicine Jacksonville, University of Florida, Jacksonville, FL.
Purpose:
Dexrazoxane has been associated with preservation of left ventricular (LV) systolic function in relatively small studies of long-term childhood cancer survivors. What remains less clear is whether this association is also seen in larger populations over time and what effect dexrazoxane has on cardiomyopathy screening recommendations.
Methods:
We analyzed echocardiographic data from participants who received doxorubicin treatment and were enrolled on Children's Oncology Group protocols P9404, P9425, P9426, P9754, and Dana Farber Cancer Institute protocol 95-01. Except for P9754, all protocols featured up-front 1:1 random assignment with dexrazoxane administered uniformly as an intravenous bolus before doxorubicin (10:1 mg/m2 dexrazoxane:doxorubicin dose). Blinded central echocardiogram remeasurements were used when possible; otherwise, data were abstracted from institutional reports. Differences and associations by ± dexrazoxane were estimated using generalized estimating equations and Cox proportional hazard models, adjusting for age, sex, doxorubicin dose, chest radiotherapy, and echocardiogram data type.
Results:
Among 895 patients (mean follow-up, 5.9 years, 230 with ≥10-year follow-up; median doxorubicin dose, 360 mg/m2; 51% dexrazoxane-exposed) with evaluable echocardiograms (n = 2,279; 1,581 centrally remeasured; 698 report only), preserved LV systolic function was observed in patients treated with dexrazoxane (z-score difference 0.4 [95% CI, 0.2 to 0.5]) versus without. Dexrazoxane was also associated with decreased hazards of reduced LV function (fractional shortening <30% or ejection fraction <50%) occurring after 1 (0.58 [95% CI, 0.41 to 0.82]) and 5 years (0.54 [95% CI, 0.31 to 0.93]) postdiagnosis. Finally, dexrazoxane appeared to decrease the incidence of reduced LV function among those classified by current cardiomyopathy screening guidelines as high risk to rates like a lower-risk group (from 40 to 21.8 events/1,000 person-years; P = .001).
Conclusion:
Dexrazoxane exerts a significant doxorubicin cardioprotective effect on LV systolic function long term and may reduce screening needs.