Which cancer treatment drugs can cause cardiomyopathy?

Cancer Treatment Drugs That Can Cause Cardiomyopathy

Anthracyclines are the most common and significant cause of chemotherapy-induced cardiomyopathy, with other agents including trastuzumab, tyrosine kinase inhibitors, proteasome inhibitors, and VEGF signaling pathway inhibitors also presenting substantial cardiotoxic risk. 1

Major Cardiomyopathic Cancer Drugs

Anthracyclines

• Doxorubicin: Causes dose-dependent cardiotoxicity
  • 5% incidence of heart failure at 400 mg/m²
  • 16% at 500 mg/m²
  • 26% at 550 mg/m²
  • 48% at 700 mg/m² 1
• Idarubicin: 5-18% incidence at doses >90 mg/m² 1
• Epirubicin: 0.9-11.4% incidence at doses >900 mg/m² 1
• Mitoxantrone: 2.6% incidence at doses >120 mg/m² 1
• Daunorubicin: Similar cardiotoxic profile to doxorubicin 1

HER2-Targeted Agents

• Trastuzumab: Causes reversible cardiac dysfunction
  • 2-7% incidence as monotherapy
  • 27% incidence when combined with anthracyclines 2
  • Mechanism: Inhibition of HER2:HER4 signaling in cardiomyocytes 1

Tyrosine Kinase Inhibitors (TKIs)

• Cause LV dysfunction particularly in patients with pre-existing cardiovascular risk factors 1

Proteasome Inhibitors

• Bortezomib and Carfilzomib: Target molecular pathways common to both cancer cells and vulnerable myocardium 1

VEGF Signaling Pathway (VSP) Inhibitors

• Bevacizumab, Sorafenib, Sunitinib: Can cause hypertension and subsequent cardiac dysfunction 1

Mechanisms of Cardiotoxicity

Anthracyclines

• Primary mechanism: Inhibition of topoisomerase 2β leading to:
  • DNA double-strand breaks
  • p53 activation
  • Cardiomyocyte death 1
• Secondary mechanisms:
  • Generation of reactive oxygen species (ROS)
  • Mitochondrial dysfunction
  • Disruption of calcium handling 3, 4

Trastuzumab

• Blocks HER2:HER4 signaling in cardiomyocytes
• Unlike anthracyclines, damage is typically reversible as it doesn't cause cardiomyocyte death 1

VSP Inhibitors

• Reduce nitric oxide formation in blood vessel walls
• Cause vasoconstriction and hypertension
• Hypertension enhances ongoing myocardial alterations 1

Risk Factors for Developing Cardiomyopathy

• High cumulative dose of anthracyclines
• Combination therapy (especially anthracyclines with trastuzumab)
• Pre-existing cardiovascular disease
• Age extremes (very young or elderly)
• Female gender
• Prior mediastinal radiation
• Hypertension
• Diabetes 1

Clinical Presentation and Monitoring

Presentation

• Early: Electrocardiographic changes, arrhythmias
• Acute: Myocarditis, pericarditis
• Late: Dilated cardiomyopathy, heart failure 3

Monitoring Recommendations

• Baseline cardiac assessment with LVEF measurement
• Regular LVEF assessments during treatment:
  • Every 3 months during and upon completion of therapy
  • Every 4 weeks if therapy is withheld for cardiac dysfunction
  • Every 6 months for at least 2 years after completion of adjuvant therapy 2
• Consider cardiac biomarkers (troponin, BNP) for early detection 1

Prevention Strategies

• Limit cumulative anthracycline dose (preferably <400 mg/m²)
• Consider alternative administration methods:
  • Continuous infusion instead of bolus
  • Liposomal formulations
  • Dexrazoxane (iron chelator) for cardioprotection 5
• Avoid concurrent use of anthracyclines with trastuzumab 1
• Aggressive management of cardiovascular risk factors
• Consider cardioprotective medications (beta-blockers, ACE inhibitors) in high-risk patients 6

Important Caveats

• Subclinical cardiac damage can occur at much lower doses than previously thought, even at 180-240 mg/m² 1
• Enhanced cardiotoxicity may occur when anthracyclines are combined with other agents like cyclophosphamide, bleomycin, cisplatin, and methotrexate 7
• Cardiotoxicity can manifest years after treatment completion, requiring long-term surveillance 1
• Withhold anthracyclines if EF <45% and trastuzumab if EF <40% 1

Understanding these cardiomyopathic effects is crucial for optimizing cancer treatment while minimizing cardiovascular morbidity and mortality in cancer survivors.