Health Effects After Anthracycline and Radiation Therapy (HEART): Dexrazoxane and Prevention of Anthracycline-related Cardiomyopathy
We will determine echocardiographic and serum biomarkers of cardiac injury in a study 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 with certain features. Our primary aim will be to determine whether patients randomized to the experimental dexrazoxane (DRZ) arms have decreased markers of myocardial injury compared with patients treated without dexrazoxane (DRZ). 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 cardiomyopathy/heart failure (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).
T-cell Acute Lymphoblastic Leukemia
Other: Diagnostic/symptom checklist
Procedure: Serum Biomarkers
Other: 6 minute walk test (6MWT)
Behavioral: Participant Questionnaires (ages ≥14 years only)
|Study Design:||Observational Model: Case Control
Time Perspective: Prospective
|Official Title:||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.
Biospecimen Retention: Samples With DNA
|Study Start Date:||March 2013|
|Estimated Primary Completion Date:||August 2017 (Final data collection date for primary outcome measure)|
Stratum 1 with diagnostic interventions
Required observations are designed to be collected at one visit:
Diagnostic/symptom checklist Anthropometry Echocardiogram Serum biomarkers Troponins (cTnT, cTnI) Natriuretic peptides (BNP, NT-ProBNP) Inflammation (hs-CRP, IL-6, TNF, Galectin-3, ST2, GDF15) Fasting glucose, lipid profile, insulin, hemoglobin AIC DNA 6 minute walk test Participant Questionnaires: Quality of life, family history, physical activity, and smoking Fasting for at least 10 hours prior to the study blood draw.
Other: Diagnostic/symptom checklist
The local PI or their designee (e.g. clinician, research nurse, or clinical research associate) will be asked to complete a diagnostic and symptom checklist (see Forms Packet on COG website) related to study outcomes. A copy of the participant's most recent clinic note and current medication list also are requested.Other: Anthropometry
Easily determined in-office physical exam parameters requested include:
Study participants will undergo a one-time standard 2D, M-mode, and Doppler echocardiogram per AHA/ACC task force practice guidelines at participating institutions (or their adult affiliates depending on patient age and institutional practice).Procedure: Serum Biomarkers
Other: 6 minute walk test (6MWT)
All participants will have the following analytes collected under standardized conditions and processed centrally.
Ambulatory participants will be asked to undergo this simple test of functional exercise capacity. Contraindications include: 1.) history of angina or myocardial infarction within the past month, 2.) resting heart rate >120 bpm, 3.) systolic blood pressure >180 mmHg or diastolic blood pressure >100 mmHg. Any other reason for patient inability to perform this test should be documented in the respective Report Form.Behavioral: Participant Questionnaires (ages ≥14 years only)
The time to complete questionnaires is estimated less than 45 minutes. General health status and quality of life will be assessed using the Short-Form-36. Participants also will be administered the Minnesota Living with Heart Failure questionnaire. Questionnaires will ascertain family history of cardiovascular and related diseases (e.g. diabetes). Physical activity will be assessed using questions from the Centers for Disease Control & Prevention's (CDC) Behavioral Risk Factor Surveillance System exercise & physical activity modules. Smoking history (current & lifetime) will be assessed using questions from Health and Nutritional Examination surveys.
Stratum 2 Relapse and subsequent malignancy status
Patients not eligible for Stratum 1 may still contribute data to the Secondary Aims:
Relapse and subsequent malignancy status
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.
|Contact: Eric J Chow, MD, MPHfirstname.lastname@example.org|
|United States, California|
|Children's Oncology Group||Not yet recruiting|
|Arcadia, California, United States, 91006-3776|
|Study Chair:||Eric J Chow, MD, MPH||Fred Hutchinson Cancer Research Center|