Prevention of Chemotherapy Induced Cardiotoxicity in Children With Bone Tumors and Acute Myeloid Leukemia
Condition: Cardiotoxicity; Acute Myeloid Leukemia in Children; Bone Tumor
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Bone Neoplasms; Cardiotoxicity
Study type: Interventional
Phase: Phase 3

Summary: 
      Prevention and early detection of chemotherapy-induced cardiotoxicity in children with bone
      tumors and Acute Myeloid Leukemia by giving capoten
    

Detailed description: 
      background and rationale: Developing countries bear the greatest burden of childhood cancers
      as over 90% of the world's children live in these countries. More effective treatment
      protocols have markedly improved the outcome of childhood cancers. The 5-year overall
      survival for children with cancer in general has improved from about 30% in 1960s to about
      80% currently. Most of current treatment protocols for childhood cancer utilize
      anthracyclines as an essential chemotherapeutic agent. However, the use of anthracyclines has
      been limited by their dose dependent cardiotoxic side-effects during and after treatment.
      Many survivors of anthracycline treatment have long-term problems because of myocardial
      damage such as impaired left ventricular contractility and cardiomyopathy, which may lead to
      overt heart failure and an increased risk of death.Anthracycline-induced clinical heart
      failure (A-CHF) is a major public health concern within the exposed population as it may not
      be manifested for many years and remains a lifelong threat. It is a particular problem in
      children treated for cancer because it is hoped that they will survive for several decades
      after treatment. As survival rates continue to improve, the resources needed to predict,
      monitor and care for survivors will also continue to increase Several risk factors have been
      already identified for anthracyclines induced cardiotoxicity. Among the non modifiable risk
      factors are age at treatment, length of survival, sex, and few genetic factors Other
      important risk factors include cumulative dose of anthracyclines, rate of administration,
      concomitant irradiation and chemotherapeutic agents Several approaches have been tried to
      prevent or minimize cardiotoxicity in cancer patients. Structural modifications of
      anthracyclines, including liposomal anthracyclines and anthracycline analogs, have been
      developed with the intention to minimize cardiovascular toxicity. Epirubicin and idarubicin,
      analogs of doxorubicin and daunorubicin, respectively, are commonly used to treat few types
      of cancer. The use of liposomal anthracyclines considerably reduces anthracycline
      cardiotoxicity but does not eliminate it. A recent meta-analysis of two studies found that
      the rates for both clinical and subclinical heart failure were significantly lower with
      liposomal anthracyclines than with conventional anthracyclines and that tumor response and
      overall survival rates did not differ significantly. Both studies were limited in scope
      because only adult women with metastatic breast cancer were included. No randomized
      controlled trials comparing liposomal with conventional anthracyclines in children have been
      published.

      Observational studies have shown that prolonged infusion of anthracyclines reduces
      cardiotoxicity than bolus infusions. However, a randomized controlled trial reported no
      statistically significant differences in echocardiographic parameters up to 8 years after
      treatment of patients receiving either continuous infusion or bolus administration.

      Dexrazoxane (the only agent proven to reduce acute cardiotoxicity in adults receiving
      anthracyclines) is not currently recommended in children due to raised concerns of increased
      incidence of secondary neoplasms.Angiotensin-Converting Enzyme Inhibitors (ACEIs) have shown
      marked reduction of toxic myocarditis in mouse models ( and have also shown marked decrease
      in adverse myocardial histopathological changes in mice treated with anthracyclines .
      Administration of ACEIs as a cardioprotective agent was studied in high risk cancer patients
      (defined by increased troponin I value) and proven to be effective . The role of ACEIs in
      prevention of anthracyclines induced cardiotoxicity was not examined before in a randomized
      controlled setting.

      Proper evaluation and early prediction of cardiotoxicity necessitates a consensus on
      sensitive and specific monitoring methods in the pediatric population. However, several
      studies have addressed the rapidly evolving issue of cardiotoxicity assessment. Several
      cardiac biomarkers have been used to monitor and predict cardiotoxicity. Among those markers
      are: Cardiac Troponin T (cTnT), Cardiac Troponin I (cTnI), Atrial Natriuretic Peptide (ANP),
      Brain Natriuretic Peptide (BNP), N-terminal pro-BNP (NT-pro-BNP), Serum Lipid Peroxide, and
      Serum Carnitine. Several systematic reviews have highlighted the difficulty of assessing
      those biomarkers due to several limitations in performed studies and high variability.
      Further research is needed to establish the effectiveness of cardiac markers in children, and
      their link to anthracycline dose, and their use in predicting individual risk for the
      development and progression of cardiotoxicity .

      However, more recent studies have shown that troponins are preferred due to their high
      sensitivity and specificity, especially when coupled with imaging modalities.

      Imaging modalities for diagnosis and follow up of cardiotoxicity are the main gold standard.
      Echocardiogram (Doppler) is the most commonly used method due its high availability and non
      invasiveness. Radionuclide Angiocardiography (RNA) including MUGA have also been used.
      Although RNA studies exhibit lower intra-individual and intra-observer variation when
      obtaining and analyzing results, but only limited information regarding diastolic function is
      obtained. RNA's also expose patients to radiation .

      A recent study has demonstrated that the use of Tissue Doppler-derived myocardial performance
      index is a more robust parameter in the detection of ventricular dysfunction caused by
      doxorubicin when compared to Doppler.

      In summary, anthracyclines induced cardiotoxicity continues to be one of the most challenging
      problems facing children with cancer during and after treatment. No current consensus exists
      about the best method for early detection and monitoring of cardiotoxicity in children with
      cancers. Troponins, echocardiography, and tissue Doppler have shown promising results as
      effective modalities but they need to be further studied especially in this specific
      population. Several protective agents have also been tried to prevent cardiotoxicity.
      ACE-Inhibitors have shown promising results in adult cancer patients, but they have not been
      studied before in the pediatric population.

      Objectives of the Study:

      Aim of the Study: (Instructions: state the goal you need to achieve) Prevention and early
      detection of chemotherapy-induced cardiotoxicity in children with bone tumors and Acute
      Myeloid Leukemia.

      Specific Objectives: (Instructions: state the details of each objective that will finally
      lead to achievement of the goal)

        1. To determine the incidence of early and late (subclinical and clinical) cardiotoxicity
           during anthracycline chemotherapy in children with Bone tumors & AML, and associated
           risk factors.

        2. To determine the role of ACE-I in preventing chemotherapy-related cardiotoxicity

        3. To determine the role of troponin I (TnI) as an early marker of cardiac toxicity .

        4. To measure the accuracy of other radiological techniques for early detection of
           cardiotoxicity like Tissue Doppler Imaging (TDI) and Speckle-tracking Echo (STE).

      Secondary Objectives: (Instructions: these are subsidiary objectives that could be studied
      during the course of the project but are not the main objectives of the study, they are
      optional and vary according to the type of the study).

        1. To standardize the monitoring, evaluation and grading of cardiotoxicity based on
           CTCAE,v4 and Modified Ross Classification.

        2. To standardize Reporting of cardiac functions using electronic sheets on Cerner for
           documentation.
    

Intervention name(s): Capoten®
Intervention type(s): Drug
Intervention description(s): ACE-I (Capoten®) will be given to patients in the Intervention arm with the start of chemotherapy, twice daily at a dose of 0.5 mg/kg/day (divided over 2 doses)
Other intervention name(s): Captopril
Intervention MeSH terms: Captopril
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: This is a prospective randomized study where all patients presenting to the CCHE with de novo diagnosis of Bone tumor (ES and OS) and AML will be randomized to receive (Intervention arm) or not to receive (Control arm) prophylactic ACE-I with the start of chemotherapy.
Masking: None (Open Label)
Primary purpose: Prevention