Longitudinal change in cardiac function after doxorubicin and dexrazoxane: A report from COG ALTE11C2.

Abstract

10010 Background: Dexrazoxane (DRZ) has been associated with reduced adverse left ventricular (LV) remodeling shortly after doxorubicin (DOX) treatment (<5y) and preserved LV function in long-term (>15y) survivors of childhood cancer. What remains less clear are longitudinal changes in echocardiographic (echo) measures in this population. Methods: ALTE11C2 analyzed participants who received DOX treatment and were enrolled on COG protocols P9404, P9425, P9426, P9754, and Dana Farber Cancer Institute 95-01. Except for P9754, all other protocols featured upfront 1:1 randomization with DRZ (10:1mg/m 2 DRZ:DOX dose). Central echo remeasurements were used when possible, otherwise we used data from abstracted echo reports. Echo values were converted to age- or BSA-specific z-scores. Differences in z-scores by ±DRZ were estimated as a function of time using generalized estimating equations, adjusting for age, sex, DOX dose, chest radiotherapy, and data type (directly remeasured vs report). Results: 895 patients (67% male; 67% white non-Hispanic; mean age at diagnosis 11.4y; median DOX dose 360 mg/m 2 ; 32% chest radiotherapy) had evaluable echo data (n=2279 echos; 1581 centrally remeasured; 698 report only; mean of 1.0-1.7 echos per patient per time period, with an average of 1.4 echos per patient ≥15y). In multivariable analysis, DRZ was overall associated with more normal LV fractional shortening and less LV end-diastolic and end-systolic dilation, a pattern consistent with less subclinical dilated cardiomyopathy directionality. These cardioprotective changes associated with DRZ were seen most clearly in patients treated with DOX ≥250 mg/m 2 with this length of follow-up. Conclusions: DRZ exerts significant DOX cardioprotective effects on cardiac function and remodeling, detectable within 5y and persisting beyond 10y of follow-up. Z-score difference by ±DRZ as a function of time, adjusted for sex, age, echo type, DOX dose, chest radiotherapy. LV measure Overall Pre-treatment <2y 2-4y 5-9y ≥10y Fractional shortening 0.4 (0.2, 0.5) * 0.1 (-0.2, 0.5) 0.1 (-0.2, 0.5) 0.7 (0.4, 0.9) * 0.5 (0.2, 0.9) * 0.4 (0.2, 0.7) * End-diastolic dimension -0.2 (-0.4, -0.1) * -0.2 (-0.4, 0.0) -0.0 (-0.3, 0.2) -0.4 (-0.6, -0.2) * -0.2 (-0.5, 0.1) -0.3 (-0.6, 0.0) * End-systolic dimension -0.3 (-0.5, -0.2) * -0.2 (-0.5, 0.0) -0.1 (-0.3, 0.1) -0.5 (-0.7, -0.3) * -0.4 (-0.7, -0.1) * -0.4 (-0.7, -0.2) * End-diastolic posterior wall thickness 0.0 (-0.1, 0.2) -0.4 (-0.7, -0.2) * -0.1 (-0.3, 0.2) 0.4 (0.2, 0.6) * 0.1 (-0.3, 0.5) 0.0 (-0.2, 0.3) End-diastolic septal wall thickness 0.1 (-0.1, 0.2) -0.2 (-0.5, 0.1) -0.1 (-0.3, 0.2) 0.3 (0.1, 0.5) * 0.2 (-0.1, 0.5) 0.2 (-0.1, 0.4) Thickness-to-dimension ratio (adverse remodeling=negative) 0.1 (-0.1, 0.2) -0.3 (-0.5, 0.0) -0.1 (-0.3, 0.2) 0.4 (0.2, 0.7) * 0.1 (-0.3, 0.6) 0.1 (-0.2, 0.4) Mass -0.1 (-0.2, 0.1) -0.4 (-0.6, -0.1) * -0.0 (-0.3, 0.2) 0.1 (-0.2, 0.3) -0.3 (-0.9, 0.3) 0.2 (-0.1, 0.6) *p<0.05.