Which chemotherapy drugs can cause cardiomyopathy?

Chemotherapy Drugs That Cause Cardiomyopathy

Anthracyclines are the primary class of chemotherapy drugs that cause cardiomyopathy, but several other agents including trastuzumab, cyclophosphamide, and tyrosine kinase inhibitors can also lead to significant cardiac dysfunction. 1

Major Cardiotoxic Chemotherapy Agents

Anthracyclines (Type I - Cumulative Dose-Related Cardiotoxicity)

• Doxorubicin: Risk increases with cumulative dose - 5% at 400 mg/m², 16% at 500 mg/m², 26% at 550 mg/m², and 48% at 700 mg/m² 1, 2
• Daunorubicin: Similar cardiotoxicity profile to doxorubicin
• Epirubicin: Lower incidence of heart failure compared to doxorubicin
• Idarubicin: Lower incidence of heart failure compared to doxorubicin
• Mitoxantrone (anthracenedione): 3-4% reduction in LVEF after one year of monotherapy 1

Targeted Therapies

• Trastuzumab: 2-7% incidence of heart failure, increasing to 27% when used concurrently with anthracyclines 1, 3
• Tyrosine Kinase Inhibitors:
  • Sunitinib: 3-15% cardiac dysfunction
  • Sorafenib: Associated with LV dysfunction
  • Pazopanib and Axitinib: 1-10% symptomatic heart failure 2

Alkylating Agents

• Cyclophosphamide: 7-28% LV dysfunction, particularly at high doses 2, 4
• Ifosfamide: Dose-dependent risk of heart failure 2, 4

Other Agents

• Paclitaxel and Docetaxel: 1.6% incidence of CHF, may enhance anthracycline cardiotoxicity 2, 4
• Fluorouracil (5-FU): Primarily causes ischemia but can lead to cardiomyopathy 1, 4
• Proteasome inhibitors (Bortezomib, Carfilzomib): Target pathways common to both cancer cells and myocardium 2

Mechanisms and Presentation of Cardiotoxicity

Anthracycline-Induced Cardiotoxicity

• Mechanism: Free radical formation, topoisomerase 2β inhibition leading to DNA damage, mitochondrial dysfunction 1
• Presentation timeframes:
  • Acute: <1% incidence, occurs during or immediately after infusion
  • Early-onset chronic: 1.6-2.1% incidence, within first year after treatment
  • Late-onset chronic: 1.6-5% incidence, occurs 1-30 years after treatment 1, 2

Trastuzumab-Induced Cardiotoxicity

• Mechanism: Inhibition of HER2 signaling in cardiomyocytes
• Unlike anthracyclines, trastuzumab cardiotoxicity is often reversible with drug discontinuation 3
• Defined as:
  • Decrease in LVEF (global or septal)
  • Symptoms of heart failure
  • Associated signs of heart failure
  • Decline in LVEF of ≥5% to <55% with symptoms or ≥10% to <55% without symptoms 3

Risk Factors for Chemotherapy-Induced Cardiomyopathy

• Cumulative dose (especially for anthracyclines)
• Combination of cardiotoxic agents (particularly anthracyclines with trastuzumab)
• Administration method (bolus vs. continuous infusion)
• Age extremes (very young or elderly >65)
• Female gender
• Pre-existing cardiovascular disease or risk factors
• Prior mediastinal radiation
• Genetic susceptibility 1, 2

Monitoring and Prevention Strategies

Monitoring

• Baseline cardiac assessment with LVEF measurement before initiating therapy
• Regular LVEF monitoring during treatment:
  • Every 3 months during and upon completion of therapy for high-risk agents
  • Every 6 months for at least 2 years following completion of adjuvant therapy 3
• Consider cardiac biomarkers (troponin, BNP) for early detection of myocardial injury 2

Prevention Strategies

• Limit cumulative anthracycline dose when possible
• Consider continuous infusions rather than bolus administration
• Use liposomal doxorubicin formulations in high-risk patients
• Consider dexrazoxane as a cardioprotective agent in selected patients
• Aggressive management of cardiovascular risk factors 2, 5
• Avoid concurrent administration of multiple cardiotoxic agents when possible 1

Important Caveats and Pitfalls

• There is no truly "safe" dose of anthracyclines - cardiotoxicity can occur even at doses as low as 100 mg/m² 1
• Cardiotoxicity may be delayed, appearing years or even decades after treatment completion 1
• Trastuzumab cardiotoxicity risk increases significantly when administered with or shortly after anthracyclines 3
• Monitoring should continue long after completion of therapy, especially for anthracyclines 2
• Early detection and prompt intervention significantly improve outcomes and functional recovery 2

By understanding which chemotherapy agents cause cardiomyopathy and implementing appropriate monitoring and prevention strategies, clinicians can minimize the cardiac morbidity and mortality associated with these life-saving cancer treatments.