Health Effects After Anthracycline and Radiation Therapy (HEART): Dexrazoxane and Prevention of Anthracycline-related Cardiomyopathy

• Left ventricular (LV) thickness-to-dimension ratio [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  A decrease in echocardiographically derived measure of pathologic left ventricle (LV) remodeling which has been shown to be an important earlier surrogate measure of subsequent heart failure in both anthracycline-exposed pediatric cancer survivors5 and in the general pediatric and adult cardiomyopathy/heart failure population. This ratio can be derived from standard measurements.
  
  

• Differences in serum biomarkers [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  Particularly cardiac troponins and natriuretic peptides associated with acute changes following anthracycline exposure will be examined. Analyses involving markers of inflammation (hs-CRP, TNF, IL6) and more novel markers associated with heart failure in the general population (galectin-3, ST2, growth differentiation factor-15) are exploratory.
  
  
• Quality of Life [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  Based on self-report instruments will be factored into QALY estimates to answer the secondary aims.
  
  
• Update primary disease relapse and second cancer rates [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  Given additional elapsed time since last follow-up used in the prior published analyses,11-13 primary disease relapse and second cancer rates will be updated.
  
  

Given the critical role anthracyclines have in many effective cancer treatments and the risk for subsequent cardiotoxicity associated with this class of agents, development of an effective cardioprotective strategy is of great importance. Although adult studies have shown that dexrazoxane (DRZ) is effective in minimizing cardiomyopathy/heart failure (CHF) after anthracycline therapy, short and long-term data in children are much more limited. Furthermore, concerns regarding DRZ's interaction with cancer therapies and possible association with an increased risk of second cancers have limited its use among children despite possible protection against premature CHF. To address these gaps in knowledge, using a cross-sectional study design, we propose to ascertain echocardiographic and serum biomarkers of cardiac injury in a cohort of long-term pediatric T-cell leukemia and Hodgkin lymphoma survivors enrolled on 3 front-line Children's Oncology Group (COG) clinical trials (POG 9404, 9425, 9426) between 1996-2001 that featured upfront DRZ randomization and a range of anthracycline exposures commonly used in contemporary therapy (100-360 mg/m2 doxorubicin). Our primary aim will be to determine whether patients randomized to the experimental DRZ arms have decreased markers of myocardial injury compared with patients treated without DRZ. Specifically, this will include a one-time measurement of an echocardiographic index of pathologic left ventricular (LV) remodeling (wall thickness-dimension ratio), complemented by serum biomarkers and a physical examination for signs and symptoms of CHF. We will also evaluate whether DRZ's cardioprotective effect is modified by anthracycline dose, chest radiation, and selected demographic factors (age at cancer diagnosis, current age, sex). In secondary analysis, we will also update the overall- and event-free survival rates between patients on the DRZ and non-DRZ arms. Finally, we will determine whether projected quality-adjusted life years differed by randomization status, accounting for premature cardiac disease, primary disease relapse, and second cancers.