Table 36: Cancer Therapies Associated with LV Dysfunction

Anti-Cancer Therapy: Anthracyclines (Doxorubicin, Daunorubicin, Idarubicin, Epirubicin, Mitoxantrone)

Major Mechanisms

  1. Reactive oxygen/free radical generation
  2. Transcriptional change in myocyte ATP pathway
  3. Decreased mRNA expression, reduced contractility
  4. Topoisomerase IIβ interference

Signs & Symptoms of Toxicity

  1. Acute Toxicity: reversible, shortly after infusion, toxicities include arrhythmias, QT prolongation +/-HF
  2. Early-onset chronic progressive: during treatment and up to 1 year post, not reversible, clinically resembles myocarditis, accompanying diastolic dysfunction
  3. Late–onset chronic progressive: >1 year from treatment, not reversible, clinical decompensation is usually preceded by occult LVD

Therapy Associated Risk Factors

  1. Greater risk for doxorubicin than for idarubicin or epirubicin
  2. IV bolus administration
  3. High peak concentrations in some studies
  4. History of irradiation
  5. Concurrent administration of cyclophosphamide, trastuzumab and/or paclitaxel
  6. Time from therapy completion
  7. Most important RF is cumulative dose

Rates of HF:

Doxorubicin 400mg/m2 = 3-5%
550mg/m2= 7-26%
700mg/m2 = 18-48%

Maximal cumulative doses (mg/m2):

Doxorubicin: 400-450
Daunorubicin: 600mg/m2
Idarubicin : 100mg/m22
Epirubicin: 800-900 mg/m2
Mitoxantrone: 160 mg/m2

References

3-12
Anti-Cancer Therapy: Cyclophosphamide

Major Mechanisms

  1. Direct endothelial injury
  2. Toxic metabolites resulting in myocardial injury
  3. Ischemia from intracapillary micro-emboli
  4. Coronary vasospasm

Signs & Symptoms of Toxicity

  1. Arrhythmias
  2. Non-specific ST-T abnormalities
  3. Pericardial effusion
  4. Hemorrhagic myopericarditis
  5. Symptomatic HF

Occurs within 1-14 days of dose administration and often last for a few days


Therapy Associated Risk Factors

  1. High dose Cyclophosphamide: 120-200mg/kg or >1.5 g/m2/day
  2. History of anthracyclines or Mitoxantrone therapy
  3. Mediastinal radiation

Toxicity related to single rather than cumulative drug dose


References

10-12
Anti-Cancer Therapy: Ifosfamide

Major Mechanisms

Proposed mechanisms similar to that of cyclophosphamide due to structural and mechanistic similarities


Signs & Symptoms of Toxicity

  1. Arrhythmias
  2. Non-specific ST-T changes on ECG
  3. HF

Acute HF typically presents within 6-23 days of first ifosfamide dose


Therapy Associated Risk Factors

  1. Potentially dose related: doses > 150mg/kg or > 12.5 g/m2

Toxicity related to single rather than cumulative drug dose


References

10, 12
Anti-Cancer Therapy: Docetaxel

Major Mechanisms

Myocyte damage


Signs & Symptoms of Toxicity

  1. HF
  2. Ischemia

References

10, 12, 14
Anti-Cancer Therapy: Sunitinib

Major Mechanisms

  1. Myocyte mitochondrial damage
  2. Impairs myocyte function in setting of hypertensive stress
  3. Reduction in nitric oxide production through VEGF inhibition
  4. AMPK inhibition

Toxicity likely reversible with stopping therapy and implementing medical management


Signs & Symptoms of Toxicity

  1. Hypertension
  2. Asymptomatic decline in LVEF
  3. Symptomatic HF

Variable time to presentation (days-months)


Therapy Associated Risk Factors

  1. Concurrent anthracycline therapy

References

6, 10, 11, 13-15
Anti-Cancer Therapy: Sorafenib

Major Mechanisms

Similar mechanism to Sunitinib. Toxicity is generally reversible and responsive to medical treatment


Signs & Symptoms of Toxicity

  1. MI
  2. Hypertension
  3. HF/LV dysfunction

Less cardiac dysfunction than Sunitinib


References

6, 10, 13, 16, 17
Anti-Cancer Therapy: Imatinib

Major Mechanisms

  1. Mitochondrial damage
  2. Protective mitochondrial pathway inhibition

Signs & Symptoms of Toxicity

  1. LV dysfunction

References

13, 15
Anti-Cancer Therapy: Dasatinib

Major Mechanisms

  1. Mitochondrial damage
  2. Protective mitochondrial pathway inhibition

Signs & Symptoms of Toxicity

  1. HF/LV dysfunction

References

13, 14
Anti-Cancer Therapy: Lapatinib

Major Mechanisms

  1. Targeting of HER1/EGFR & HER2 receptors

Signs & Symptoms of Toxicity

  1. LV dysfunction
  2. Symptomatic HF
  3. QTc prolongation

Relatively low incidence of adverse cardiac events


Therapy Associated Risk Factors

  1. Prior anthryacyline or trastuzumab therapy

References

11, 14
Anti-Cancer Therapy: Trastuzumab

Major Mechanisms

  1. Inhibition of HER2 (Erbβ2) signaling may interfere with growth and signaling of cardiomyocytes and may induce mitochondrial damage

Toxicity is generally reversible


Signs & Symptoms of Toxicity

  1. HF/LV dysfunction

Therapy Associated Risk Factors

  1. Concurrent paclitaxel or anthracycline based therapy
  2. Cumulative anthracycline dose >300mg/m2)
  3. Concomitant use of antihypertensive drugs

Toxicity is generally not dose related


References

10, 11
Anti-Cancer Therapy: Bevacizumab

Major Mechanisms

  1. Inhibition of VEGF signaling resulting in uncontrolled HTN
  2. Risk of HF through impaired adaptive response to pressure overload
  3. Decreased NO and prostacyclin production and expose vascular collagen to tissue factor increasing risk of thrombosis

Signs & Symptoms of Toxicity

  1. HTN
  2. HF
  3. MI/Angina
  4. ATE

Therapy Associated Risk Factors

  1. Concurrent anthracycline therapy

ATE events not believed to be associated with dose or cumulative exposure


References

10, 11, 18-21
Anti-Cancer Therapy: Anti-Cancer Therapy: Radiation therapy

Signs & Symptoms of Toxicity

  1. CAD
  2. Valvular disease
  3. Pericardial disease
  4. Restrictive cardiomyopathy
  5. Conduction system disease

References

6, 7
AC, doxorubicin & cyclophosphamide;
AMPK, adenosine monophosphate-activated protein kinase;
ATE, arterial thrombotic event;
ATP, adenosine triphosphate;
AV, atrio-ventricular;
CAD, coronary artery disease;
DHP, dihydropyrimidinase;
ECG, electrocardiogram;
CMP, cardiomyopathy;
EGFR, epidermal growth factor receptor;
HER1 and HER2, human epithelial growth factor receptor 1 and 2;
LVD, LV dysfunction;
LVEF, LV ejection fraction;
MI, myocardial infarction;
NO, nitric oxide;
VEGF, vascular endothelial growth factor;