Athracycline Induced Cardiomyopathy: Mechanisms and Prevention

1
Athracycline Induced Cardiomyopathy Mechanisms
and Prevention

• David Kuperman, M.D.
• Hematology/Oncology Fellow
• September 17, 2004

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Case Report

• Ms. BD is a 53 y/o woman who initially presented
  in 5/03 with progressive fatigue.
• She was found to be pancytopenic.
• Her past medical history is significant for
  ovarian carcinoma s/p hysterectomy and
  oopherectomy,hypertension, and diabetes mellitus.

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Case Report

• She had a bone marrow biopsy performed which
  showed AML-M2.
• She received induction chemotherapy per CALGB
  protocol 19808 with cytarabine, daunorubicin,
  and etopside.
• Her MUGA prior to therapy showed an ejection
  fraction of 64

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Case Report

• She achieved remission and was consolidated with
  high dose cytarabine.
• In 9/03, she came was admitted for cough and
  neutropenic fever.
• In the course of working up her cough, she was
  found to have developed a dilated cardiomyopathy
  with an EF of 15.

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Case Report

• At this time, her counts are normal and she has
  no evidence of leukemia.
• She does, however, have severe congestive heart
  failure requiring a continuous milrinone drip.

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Introduction to athracyclines

• Athracyclines are substances that were originally
  isolated from Streptomyces peucetius for use as
  antibiotics.
• They have been found to have broad anti-tumor
  activity and have been used for more than 30
  years.
• Athracyclines have multiple mechanisms of action.

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Introduction to athracyclines

• They intercalate between base pairs and inhibit
  DNA and RNA synthasis.
• They also prevent DNA repair by action on
  topoisomerase II
• Commonly used athracyclines are daunarubicin,
  doxorubicin, epirubicin, and mitoxantrone.

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Introduction to athracyclines

• The major dose limiting toxicity of athracyclines
  is the cardiotoxicity.

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Athracycline Cardiotoxicity

• This can be divided into acute and chronic
  toxicities.
• The acute toxicities which occur with or
  immediately following transfusion are rare and
  include arrhythmia and myocarditis
• These are usually transient.

10
How is the cardiotoxicity manifested?

• The chronic toxicity is primarily destruction of
  myocytes leading to congestive failure.
• The cardiomyopathy is irreversible.
• It is more common than the acute toxicities.

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Risk Factors

• The most important risk factor is cumulative dose
• A cumulative dose of 700 mg/m2 of doxorubicin is
  associated with a 48 risk, a 550 mg/m2 dose has
  a risk of 26, and a dose of less than 400 mg/m2
  is about 5

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Risk Factors

• Mediastinal radiation
• Administration of other cardiotoxic medications
• Young or old age
• Previous heart disease

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Mechanisms of toxicity

• Multiple mechanisms appear to be involved
• Athracyclines appear to accumulate in the heart
  because of the high levels of cardiolipin
• Oxidative stress seems to be one of the most
  important
• The oxidative stress occurs when either the
  athracycline or a metabolite is reduced by a
  flavoenzyme

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Mechanisms of toxicity

• The heart is predisposed to oxidative stress
  because of relatively low levels of antioxidant
  enzymes
• Calcium overload within the cell is also reported
• A direct affect of the immune system has also
  been suggested

16
Determination of toxicity

• Cardiac imaging by echocardiogram or MUGA
• Elevations of troponins in children have been
  useful but not so much in adults
• Naturietic peptide levels have also been measured
  with mixed results

17
Prevention

• Minimize athracycline dose
• Use different dosing schedules
• Use different forms of athracyclines that cause
  less cardiotoxicity
• Use agents to prevent the cardiotoxicity

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Dosing Schedules

• There is some data to suggest that continuous
  infusion has less cardiac toxicity
• 62 patients with either breast or ovarian CA
  were randomized to receiving either bolus
  doxorubicin or the same dose with a six hour
  infusion.
• There was a significant difference in decrease in
  EF. At 400 mg/m2, the decrease in the bolus group
  was 21 versus 6 in the slow infusion group.

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Dosing Schedules

• Unfortunately, we do not as of yet have large
  randomized trials comparing the treatment
  effectiveness of slow infusion athracyclines vs.
  bolus.
• We also lack long term follow up data.

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Liposomal preparations of athracyclines

• Liposomal preparations of athracyclines also show
  promise in reduction of cardiac toxicity
• Liposomes are preferentially taken up by tissues
  enriched in phagocytic reticuloendothelial cells

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Liposomal preparations of athracyclines

• In a retrospective analysis of 8 phase I and II
  clinical trials, there was not a clinically
  significant decrease in EF in 41 patients treated
  with 500 mg/m2
• In many trials, it appears to be as effective as
  standard doxorubicin

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Liposomal preparations of athracyclines

• Liposomal preparations, however, may be
  associated with more mucositis andpalmoplantar
  erythrodysesthesia

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Dexrazoxane

• Dexrazoxane is an oral iron chelator
• It prevents the formation of the semiquinone-iron
  which leads to reactive oxygen production
• It has been tested in multiple clinical trials
  and has been shown to reduce cardiac toxicity

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Dexrazoxane and Cardiotoxicity

• In 2 randomized controlled trials performed in
  metastatic breast cancer, 289 patients being
  treated with FDC and 249 were FDC dexrazoxane.
• Symptomatic CHF developed in 8 of the placebo
  group versus 1 of the dexrazoxane group

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Dexrazoxane and Cardiotoxicity

• Similar results were seen in other trials using
  FEC for metastatic breast cancer and epirubicin
  for sarcoma

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Dexrazoxane and response to chemotherapy

• Some data suggests that dexrazoxane may decrease
  response to chemotherapy
• One phase III trial published by Swain in 1997
  showed a significant decrease in response in the
  dexrazoxane group.
• There has been no difference in overall survival
  or progression free survival in this trial

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Dexrazoxane and response to chemotherapy

• A metanalysis of 818 patients showed no
  difference in response
• Perhaps the abnormality was in the response rate
  to placebo

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ASCO Recommendations

• Not recommended for initial therapy
• Breast patients receiving more than 300 mg/m2 of
  doxorubicin
• Consideration in patients with other malignancies
  receiving more than 300 mg/m2 of doxorubicin

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Future directions

• Further evaluation of current agents
• Statins
• ACE inhibitors

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References

• S. Jeffers et alia, Pegylated liposomal
  doxorubicin (doxil) reduced clinical
  cardiotoxicity in patients reaching or exceeding
  cumulative doses of 500 mg/m2. Ann. Oncol. 11
  (2000), pp. 10291033.
• S.S. Legha et alia, Reduction of doxorubicin
  cardiotoxicity by prolonged continuous
  intravenous infusion. Ann Intern Med 96 (1982),
  pp. 133-139.
• K.J. Schimmel et alia, Cardiotoxicity of
  cytotoxic drugs. Cancer Treatment Reviews 30
  (2004), pp. 181-191.

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References

• L. Seymour et alia, Use of dexrazoxane as a
  cardioprotectant in patients receiving
  doxorubicin or epirubicin chemotherapy for the
  treatment of cancer. Cancer Prev Control 3
  (1999), pp. 145159.
• J. Shapira et alia, Reduced cardiotoxicity of
  doxorubicin by a 6-hour infusion regimen. A
  prospective randomized evaluation.Cancer 65
  (1990), pp. 870-873.
• P.K. Singal, Doxorubicin-induced cardiomyopathy.
  NEJM 339 (1998), pp. 900-905 J.L. Speyer et alia,
  Prospective evaluation of cardiotoxicity during a
  six-hour doxorubicin infusion regimen in women
  with adenocarcinoma of the breast . American
  Journal of Medicine 78 (1985), pp. 555-563.

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References

• S.M. Swain et alia, Cardioprotection with
  dexrazoxane for doxorubicin-containing therapy in
  advanced breast cancer. J Clin Oncol 15 (1997),
  pp. 13181322.
• S.M. Swain et alia, The current and future role
  of dexrazoxane as a cardioprotectant in
  anthracycline treatment expert panel review. J
  Cancer Res Clin Oncol 130 (2004), pp. 1-7.
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