Adriamycin induced cardiomyopathy

1
Adriamycin induced cardiomyopathy

• G.A.Prasad MD
• Sinai Samaritan Medical Center
• Milwaukee, WI

2
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.

3
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.

4
Incidence

• CHF developed in lt 4 of patients who had
  received a cumulative dose of 500 to 550 mg of
  doxorubicin /m2, lt 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.

5
Risk-Factors for Doxorubicin Induced
Cardiomyopathy

• Age gt 70 yr
• Combination therapy
• Mediastinal radiotherapy (previous or
  concomitant)
• Previous cardiac disease (coronary, valvular,
  ormyocardial)
• Hypertension
• Liver disease
• Whole-body hyperthermia

6
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.

7
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.

8
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

9
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.

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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.

11
loss of myofibrils and the vacuolization of
cytoplasmcharacteristic of doxorubicin induced
myopathy
12
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.

13
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

14
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.

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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.

16
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.

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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.

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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.

19
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.

20
Treatment

• Options similar to other cardiomyopathies
• diuretics
• ace inhibitors
• beta blockers
• Only curative option is heart transplantation.

21
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.

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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.

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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.

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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