Adriamycin Induced Cardiomyopathy by H8tRHS8

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									Adriamycin induced
 cardiomyopathy
        G.A.Prasad MD
Sinai Samaritan Medical Center
        Milwaukee, WI
Doxorubicin (Adriamycin)
   Has been used in oncologic practice since the late
    1960s.
   The tumors most commonly responding to
    doxorubicin include breast and esophageal
    carcinomas; osteosarcoma, Kaposi's sarcoma, and
    soft-tissue sarcomas; and Hodgkin's and non-
    Hodgkin's lymphomas.
   However, reports of fatal cardiotoxic effects of
    doxorubicin have subdued enthusiasm for this
    drug.
Incidence
   In a retrospective study of 399 patient records,
    cardiomyopathy and congestive heart failure
    were dose-dependent.
   Incidence rose to unacceptably high levels
    when the cumulative dose of the drug
    exceeded 550 mg per square meter of body-
    surface area.
Incidence
   CHF developed in < 4 % of patients who had
    received a cumulative dose of 500 to 550 mg of
    doxorubicin /m2, < 18% at a dose of 551 to 600
    mg/m2 and to about 36% at a dose of 601 mg/m2
   An empirical dose limit of 500 mg/m2 was
    suggested as a strategy to minimize the risk of
    cardiomyopathy.
   CMP has been reported to develop at a cumulative
    dose of doxorubicin of less than 500 mg/m2.
Risk-Factors for Doxorubicin
Induced Cardiomyopathy
   Age > 70 yr
   Combination therapy
   Mediastinal radiotherapy (previous or
    concomitant)
   Previous cardiac disease (coronary, valvular, or
    myocardial)
   Hypertension
   Liver disease
   Whole-body hyperthermia
Cause ??
   The chemical structure of doxorubicin is prone to
    the generation of free radicals, and the oxidative
    stress that results correlates with cellular injury.
   Doxorubicin administration is associated with a
    decrease in the presence of the endogenous
    antioxidants responsible for the scavenging of free
    radicals.
   A decrease in antioxidants and an increase in
    oxidants (free radicals) result in increased
    oxidative stress, leading to myocardial damage.
Diagnosis
   The standard clinical approach to monitoring for
    doxorubicin cardiotoxicity :
    • assessment of base-line cardiac performance before
      doxorubicin therapy begins
    • regular monitoring during treatment, and follow-up
      after therapy has been completed.
   The insidious nature of doxorubicin-induced CMP
    is best observed in the transient improvement in
    cardiac performance after the completion of
    therapy, followed by the development of full-blown
    CMP with CHF after years of latency.
    Diagnostic Procedures                          Characteristics
   physical examination and history taking         lack of specificity
   electrocardiography: arrhythmias, flattening    lack of specificity
    of T-wave, prolongation of QT interval,
    decrease in R-wave voltage
   serial echocardiography and radionuclide        high reliability
    imaging: decrease in left ventricular           wide use and
    ejection fraction                               availability
   angiography with radiolabeled anti-             high sensitivity
    myosin antibody                                 for cell necrosis;
                                                    low specificity
   angiocardiography with metaiodobenzyl-          high sensitivity for
    guanidine                                       myocardial neural
                                                    integrity and cardiac
                                                    function
                                                    low specificity
   endomyocardial biopsy                           greatest reliability
                                                    high expense
Echo and MUGA
   One advantage of echocardiography over
    radionuclide imaging is that it does not expose
    patients to ionizing radiation.
   The sensitivity of EF studies for the detection of
    subclinical early cardiomyopathy becomes even
    higher when they are combined with exercise
    stress testing.
   Therefore, study of the EF should be part of the
    routine care of patients receiving doxorubicin
    treatment.
Endomyocardial Biopsy
   The diagnostic test with the greatest specificity
    and sensitivity for doxorubicin-induced
    cardiomyopathy is endomyocardial biopsy.
   These histologic markers are used to grade injury
    on a scale of 1 to 3)
    A biopsy score of 2.5 or higher may be
    considered to indicate that doxorubicin therapy
    should be terminated.
loss of myofibrils and the vacuolization of cytoplasm
characteristic of doxorubicin induced myopathy
Endomyocardial Biopsy
   However, in patients with low-grade myocardial
    damage and no substantial changes in the ejection
    fraction at the completion of therapy, it is still
    possible that CHF with typical features of
    doxorubicin-induced cardiomyopathy will develop
    4 to 20 years later.
   Until we learn the full implications of the biopsy
    scores through long-term follow-up study, caution
    should be exercised when this system is used as a
    guide for the continuation or termination of therapy.
Mx: Prevention
   Patients with cancer in whom symptoms of
    cardiomyopathy developed within the first year
    after doxorubicin therapy may have had an
    improvement in their condition during the first
    four years, but it subsequently deteriorated, and
    they died six to eight years later.
   Hence prevention is of utmost importance
Prevention
   Strategies that have been used in an attempt to
    prevent doxorubicin-induced CMP ,include
    • the use of doxorubicin analogues
    • limits on the amount of drug used
    • alternative drug-delivery methods
    • and administration of doxorubicin in
      combination with cardioprotective agents.
    None of these approaches have had more than
    limited success.
Doxorubicin analouges
   Various analogues of anthracycline (including
    carminomycin, detorubicin, esorubicin,
    marcellomycin, quelamycin, and rodorubicin) are
    available.
   However, none of these agents have any
    advantage over doxorubicin.
    There are other analogues of anthracycline; (e.g.,
    idarubicin, epirubicin). Their advantage over
    doxorubicin on an equimolar basis is also unclear.
Alternative modes of delivery
   When used as a single agent, doxorubicin is
    administered by rapid intravenous infusion
    (within a 15-to-20-minute period), and the
    recommended dose (60 to 75 mg per square
    meter) is given every three weeks.
   The effects of this standard rapid infusion were
    compared with those of continuous infusion
    over a six-hour period in a prospective,
    randomized study of doxorubicin treatment for
    metastatic carcinoma of the breast or ovary.
Alternative modes of delivery
   Significantly greater decreases in the EF were
    detected in patients receiving the standard
    infusion
   A reduction in cardiotoxicity was observed in
    patients who received an even higher dose of
    doxorubicin (600 mg /m2) as a continuous
    infusion over a period of 48 to 96 hours, as
    compared with those who received a median of
    465 mg /m2 as a standard rapid infusion.
Cardioprotective agents
   Administration of doxorubicin in combination
    with agents that would block its free-radical-
    mediated cardiotoxic effect, and yet not interfere
    with its antineoplastic effect has been another
    goal.
    Several agents, including dexrazoxane (ICRF-
    187) and amifostine, have been tried, but with
    limited success.
Cardioprotective agents
   Dexrazoxane ( an iron chelating agent ) has
    been studied the most :
    • has shown some reduction in incidence of
      acute myocardial injury
    • but associated severe myelosuppression
    • may interfere with antitumor activity of
      doxorubicin??
   Needs more study.
Treatment
 Options similar to other cardiomyopathies:
  • diuretics
  • ace inhibitors
  • beta blockers
 Only curative option is heart transplantation.
Future prospects
   Prevention of oxidative-stress injury, a
    complication inherent in repeated administration of
    doxorubicin, is an avenue worth pursuing.
   Probucol, a lipid-lowering drug, is known to act as
    an antioxidant as well as to promote the activities
    of endogenous antioxidants.
    Hope is offered by a recent experiment in animals
    in which probucol, prevented doxorubicin-induced
    CMP without compromising the antitumor benefits
    of the drug.
Conclusions:
   Despite its dose-dependent cardiotoxic effects,
    doxorubicin remains in use because of its efficacy
    in the treatment of several types of tumors.
   Its cardiotoxicity can be reduced by limiting the
    peak plasma concentration in each treatment with
    the use of a slower infusion as well as by limiting
    the overall cumulative dose.
   Endomyocardial biopsy is expensive, but it
    remains the most sensitive method for early
    diagnosis of ensuing cardiomyopathy.
Conclusions:
   A change in the LVEF, as determined by
    echocardiography or radionuclide imaging, is a
    very good indicator of developing CMP
   Monitoring for such a change should be
    frequent during treatment and regular thereafter,
    throughout the patient's lifetime.
Conclusions:
   According to Steinherz et al., echocardiography
    should be performed before every additional course
    of doxorubicin up to a total dose of 300 mg per
    square meter, given with or without concurrent
    radiation therapy.
   MUGA scan should also be performed if the
    patient is receiving more than 400 mg per square
    meter in one course.
   Echocardiography should be repeated 3, 6, and 12
    months after the completion of therapy and every 2
    years thereafter

								
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