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Late Effects





Cardiac damage may be related to:


Radiation therapy (RT):

The severity of RT induced heart disease depends on:

Treatment factors:

  • Total dose RT:
    • The higher the dose, the greater the risk of damage15
    • Usually greater than 35 Gy dose to the heart increases the risk of cardiomyopathy2
  • Fractionation (how the radiation was “split up” into daily treatments)15
    • Large fraction sizes:
      • Daily dose fraction > 2 Gy/day are associated with an increased risk of damage to normal tissues2
  • The amount (volume) and regions of the heart included in the RT treatment volume15
  • RT technique
    • How the RT was planned and administered
    • Treatment was sometimes “weighted” anteriorly in mantle fields to treat HL.  Relatively more RT was given to the anterior chest and there was an increased risk of cardiac damage and pericarditis
  • Cardiotoxic chemotherapeutic agents given concurrently with the radiotherapy increases the risk15
  • Completion of RT prior to 19702
    • Probably related to treatment technique and length of follow up

Patient Factors:

  • Very young children are at increased risk
  • Length of follow up important
    • The longer patients are followed, the more likely they are to have these problems
  • Associated preexisting cardiac risk (hypertension, coronary artery disease, left ventricular dysfunction) increases the risk of late cardiac toxicity2
  • Pregnancy2
    • This increases cardiac stress and previously unrecognized cardiomyopathy becomes obvious.
  • Engaging in extreme/competitive athletics2



Drugs associated with cardiomyopathy:

1. Anthracyclines:
  a. Doxorubicin (Adriamycin)
  b. Daunorubicin
  c. Idarubicin

Adriamycin is by far the commonest cause of late cardiomyopathy

The risk of this complication with anthracycline therapy depends on:

Treatment Factors:

  • Type of Anthracycline
  • Cumulative dose of anthracycline
    • Most significant risk factor
    • The higher the cumulative dose the greater the risk:
      • Risk:
      • 4% at a cumulative dose of 500 to 550 mg/m2 of doxorubicin
      • 18% at 551 to 600 mg/m2
      • 36% for cumulative doses of >600 mg/m2
    • Higher cumulative anthracycline doses associated with
      • Increased afterload
      • Decreased contractility
    • Though risk increases with cumulative dose the relationship between dose and risk of cardiotoxicity is not linear.
    • There are reports of cardiac dysfunction for patients who have received less than 300 mg/m2
    • There is no absolutely safe dose of anthracycline
  • Rate of drug administration
    • Higher rate may increase risk of cardiotoxicity (though recent studies have failed to show that this is an important factor).
  • Use of cardioprotectants
  • Mantle RT and concurrent chemotherapy
    • Trend towards increased cardiac damage with concurrent:
      • RT
      • cyclophosphamide
      • bleomycin
      • vincristine
      • mitoxantrone


Patient Factors:

Different patient factors increase the risk of cardiotoxicity:

  • Patient age
    • Young age (less than 4 years) at time of therapy increases risk
  • Pharmacogenomic characteristics
  • Down's syndrome (Trisomy 21)
    • Increased risk of early cardiotoxicity
  • Gender
    • Girls more at risk for cardiac damage
  • Race
    • Increased risk for African-American patients
  • Length of follow up
    • The longer patients are followed, the more likely they are to have cardiotoxicity
  • Other coexisting medical conditions:
    • Endocrine problems
    • Hypothyroidism/hyperthyroidism
    • Growth hormone deficiency
    • Diabetes
    • Liver disease
    • Underlying other cardiac abnormalities


Disease factors:

  • The tumor may be directly involving the heart.

2. Alkylating agents (such as Cyclophosphamide and Ifosfamide - often high dose in the setting of stem cell transplant)

Cyclophosphamide and Ifosfamide (usually when given at higher total doses and along with other cardiotoxic drugs)14can result in acute toxicity with:

  • congestive cardiac failure and pleural effusion
  • chest pain
  • ECG changes and arrhythmias

3. Antimetabolites (such as Fluorouracil and Cytarabine)

Fluorouracil and cytarabine when given with other cardiotoxic drugs or with concurrent cardiovascular disorders can occasionally cause angina, MI, hypotension, ECG changes, pericarditis, CHF and arrhythmias.

4. Antimicrotubule agents (such as Pacilaxel and Etoposide)

Pacilaxel and etoposide when given with other cardiotoxic drugs or with concurrent cardiovascular disorders can possibly result with sinus bradycardia/bradyarrhythmias, MIs, other arrhythmias s, hypotension and ECG changes.

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