Magnetic Resonance Imaging:A Window to Anthracycline Toxicity
Condition: Cardiac Complications
Study type: Observational

Summary: 
      The study is being conducted to see which cardiac tests that monitor how the heart functions
      during and after treatment with anthracyclines are most effective. This study will assess a
      new way to check the heart function of children during and after cancer treatment. Currently,
      doctors use echocardiograms (heart ultrasound) to see how the heart is working.
      Echocardiograms are currently being done as part of standard of care prior to giving
      anthracycline chemotherapy doses and if any cardiac problems are suspected. The new method
      involves Cardiac Magnetic Resonance Imagining (CMRI) and a blood tests for certain biomarkers
      for heart health: High sensitivity troponin, Caspase, C-reactive Protein (CRP), ventricular
      derived B-type natriuretic peptide (BNP), Matrix Metalloproteinases (MMPs), Tissue inhibitors
      of metalloproteinases (TIMPs), C terminal propeptide of type I procollagen (PICP), C terminal
      telopeptide of collagen type I (CITP), Troponin I, and Bone Alkaline Phosphatase. The purpose
      of this study is to find out if CMRI and blood tests help us to find heart problems earlier,
      before they are detected by echocardiograms.
    

Detailed description: 
      This is a pilot study with a descriptive study design.

      Anthracycline induced late onset cardiotoxicity, defined in terms of abnormal findings on
      echocardiography, has been reported to occur in 57% of childhood cancer survivors. Serial
      monitoring of cardiac function by means of echocardiography detects cardiac toxicity only
      when many of the cardiomyocytes have already been damaged. Given the lack of evidence to
      support the reliability of serum markers of cardiotoxicity, many recommend modifying the dose
      of anthracyclines only when there is objective evidence of myocardial dysfunction by
      echocardiograph. This approach could be responsible for the increasing frequency of dilated
      cardiomyopathy occurring 10-15 years after treatment. Non invasive imaging methods are thus
      critically needed to more precisely detect cardiotoxic changes in children receiving
      anthracyclines. CMRI has become the gold standard for the assessment and quantification of
      ventricular volumes, myocardial mass and global and regional wall function. CMRI also allows
      morphologic analysis of the myocardium as well as detection and characterization of
      pathological myocardium. In this study, the investigator therefore proposes to use serial MRI
      parameters in conjunction with a battery of serologic markers, obtained at intervals
      determined by cumulative anthracycline dose, to monitor changes in systolic function during
      chemotherapy and one year after the end of chemotherapy. The investigator will use a
      combination of a serum cardiac biomarker of inflammation (CRP), myocyte injury (Troponin,
      Caspases), heart failure (BNP), and extracellular matrix remodeling (PICP, CITP, Bone
      Alkaline Phosphatase, MMPs, TIMPs). The investigator will then correlate these findings with
      CMRI parameters of myocyte dysfunction. Results will be compared with standard
      echocardiography. The investigator predict that CMRI is a better indicator of early
      anthracycline cardiotoxicity in children with solid tumors and hematologic malignancies.

      Patients who are of age 9 years of age or older, newly diagnosed with a malignancy that is
      anticipated to receive high dose anthracyclines as part of their chemotherapy (such as but
      not limited to solid tumors, high risk Acute Lymphocytic Leukemia, Acute Myelogenous
      Leukemia, and lymphomas) will be invited to participate in the study.

      Specific Aim 1: To use CMRI to detect occult asymptomatic cardiotoxicity over time and in
      relation to cumulative dose among pediatric cancer patients treated with anthracyclines.

      Specific Aim 2: To quantitate serologic biomarker profile for several functional pathways
      including the inflammatory cascade, MMP/TIMP remodeling pathways, signaling, cell viability
      and growth domains over time and in relation to cumulative dose among pediatric cancer
      patients treated with anthracyclines.

      Specific Aim 3: To compare changes over time detected by CMRI and serologic markers of
      cardiac toxicity to echocardiographic indices of systolic and diastolic function and
      determine their ability alone or in combination to predict freedom from left ventricular
      dysfunction defined as change in ejection fraction at one year post chemotherapy.

      These aims will test the hypothesis that CMR imaging and serologic biomarkers of
      inflammation, apoptosis and progressive extracellular matrix remodeling will precede
      echocardiographic indices of systolic and diastolic function among children receiving high
      dose anthracyclines as part of their chemotherapy protocol.

      Study Outcome Measures

      Myocardial edema in the acute phase measured by the following parameters:

        -  Increased myocardial mass.

        -  Focal areas of high signal intensity T2 weighted spin echo imaging and myocardial
           delayed enhancement. Significant enhancement will be defined as signal intensity
           increases of greater than two standard deviations above the mean value of remote normal
           myocardium.

        -  Increased myocardial T2 relaxation time in the myocardium compared to baseline as
           measured by T2 mapping technique

        -  Changes in myocardial T1 relaxation time in the myocardium pre and post-contrast
           compared to baseline as measured by T1 mapping technique (Modified Look-Locker inversion
           recovery (MOLLI). Myocardial T1 (msc).

        -  Decrease in myocardial strain and strain rate compared to baseline calculations: Mid
           wall left ventricular circumferential strain (ECC), Maximum longitudinal left
           ventricular strain (ELL).

        -  Decrease in myocardial T2* indicative of presence of Iron in the myocardium (reflecting
           anthracycline-Fe complexes)(ms).

        -  The following markers were measured: Matrix/Fibrosis pathway:

      Plasma levels of MMPs (all soluble MMP types) and TIMPs (all 4 TIMPs); Inflammatory domain:
      cytokines (TNFα, interleukins, interferon gamma (IFNG), TGF β2, TGF βII)),cytokine receptors
      (sTNF RI, sTNF RII, sSt2, sgp130, siL1-RII/sCD121b, siL-2Rα/CD25, siL-4R, siL-6R, Endoglin);
      Signaling pathway: growth factors (GDP-15, GCSF, VEGF, sVEGFR2 TGFβ1, IGF-1;). Changes in
      regional myocardial function and elevation of serologic markers may predict freedom from left
      ventricular dysfunction defined as ejection fraction ≥55% at 1 year.

      The following tests and procedures will be done for this study:

        1. CMRI tests

        2. Blood tests

        3. Echocardiograms

      These tests noted above will be done:

        1. Prior to or at before the cum dose of anthracyclines = 60 mg/m2

        2. Cumulative anthracycline doses:

             -  125-175 mg/m2

             -  200-250 mg/m2

             -  275-325 mg/m2

             -  After maximal anthracycline treatment

             -  One year after completion of maximal anthracycline therapy

      The blood tests being done are:

      Matrix/Fibrosis pathway:Plasma levels of MMPs (all soluble MMP types) and TIMPs, (all 4
      TIMPs); Inflammatory domain: cytokines (TNFα, interleukins, interferon gamma (IFNG), TGF β2,
      TGF βII)), Cytokine receptors (sTNF RI, sTNF RII, sSt2, sgp130, siL1- RII/sCD121b,
      siL-2Rα/CD25, siL-4R, siL-6R, Endoglin); Signaling pathway: growth factors (GDP-15, GCSF,
      VEGF, sVEGFR2 TGFβ1, IGF-1;
    

Observational model: Case-Only
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Age group is greater than or equal to 9 years of age, have a cancer diagnosis that will be
        treated with anthracyclines
      
Biospecimen description: 
      Pending
    
Keywords: Cancer treatment; Anthracyclines; Cardiac MRI