What anti-neoplastic (anti-cancer) drugs can cause cardiomyopathy?

Antineoplastic Drugs That Cause Cardiomyopathy

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

Anthracyclines

Anthracyclines represent the most well-established class of cardiotoxic chemotherapeutic agents:

• Doxorubicin: Dose-dependent cardiotoxicity with 5% incidence of heart failure at 400 mg/m², increasing to 16% at 500 mg/m², 26% at 550 mg/m², and 48% at 700 mg/m² 1
• Daunorubicin: Similar cardiotoxic profile to doxorubicin 1
• Epirubicin: 0.9-11.4% incidence of cardiotoxicity at doses >900 mg/m² 1
• Idarubicin: 5-18% incidence of cardiotoxicity at doses >90 mg/m² 1
• Mitoxantrone (anthracenedione): 2.6% incidence of cardiotoxicity at doses >120 mg/m² 1; recent evidence suggests it is 10.5 times more cardiotoxic than doxorubicin, significantly higher than the previously assumed 4:1 ratio 2

Mechanism of Anthracycline Cardiotoxicity

Anthracyclines cause cardiotoxicity through multiple mechanisms:

• Inhibition of topoisomerase 2β leading to DNA double-strand breaks and p53 activation 1
• Generation of reactive oxygen species (ROS) causing oxidative stress 3
• Disruption of mitochondrial structure and function 3
• Changes in calcium homeostasis affecting contractility 3

Targeted Therapies

HER2-Targeted Agents

• Trastuzumab: Causes reversible cardiac dysfunction by blocking HER2:HER4 signaling in cardiomyocytes 1. Clinical trials report cardiac dysfunction rates of 7-34%, with heart failure (NYHA class III or IV) rates between 0-4% 3

VEGF Inhibitors and Tyrosine Kinase Inhibitors

• Bevacizumab: 2% incidence of LV dysfunction and 1% incidence of heart failure 3
• Sunitinib, Pazopanib, Axitinib: Cardiac dysfunction in 3-15% of patients and symptomatic heart failure in 1-10% 3
• Sorafenib, Vandetanib: Also associated with cardiac dysfunction 3

These agents primarily cause cardiotoxicity by reducing nitric oxide formation in blood vessel walls, leading to hypertension and subsequent cardiac dysfunction 1

Other Cardiotoxic Agents

Alkylating Agents

• Cyclophosphamide: Associated with LV dysfunction in 7-28% of patients, particularly at high doses (≥150 mg/kg and 1.5 g/m²/day) 3
• Ifosfamide: Can induce heart failure, with a dose-response trend (doses ≥12.5 g/m²) 3

Microtubule Inhibitors

• Paclitaxel and Docetaxel: Relatively low incidence of heart failure; in one trial, docetaxel-doxorubicin-cyclophosphamide was associated with 1.6% incidence of CHF 3

Proteasome Inhibitors

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

Risk Factors for Chemotherapy-Induced Cardiomyopathy

Several factors increase the risk of developing cardiomyopathy:

• Cumulative anthracycline dose: The strongest predictor of cardiotoxicity 3, 1
• Combination therapy: Particularly anthracyclines with trastuzumab 3, 1
• Age extremes: Both pediatric patients and those >65 years 3
• Female sex 3
• Pre-existing cardiovascular disease 1
• Prior or concomitant mediastinal radiation 3, 1
• Hypertension and diabetes 1
• Renal failure 3

Prevention and Monitoring

• Limit cumulative anthracycline dose when possible 1
• Consider dexrazoxane for patients who have received a cumulative doxorubicin dose of 300 mg/m² and will continue doxorubicin therapy 4
• Avoid concurrent use of anthracyclines with trastuzumab 1
• Perform baseline cardiac assessment with LVEF measurement and regular monitoring during treatment 1
• Consider cardiac biomarkers (troponin, BNP) for early detection of cardiotoxicity 1
• Long-term surveillance is essential as cardiotoxicity can manifest years after treatment completion 1

Clinical Implications

• Subclinical cardiac damage can occur at much lower anthracycline doses than previously thought (even at 180-240 mg/m²) 1
• Consider withholding anthracyclines if EF <45% and trastuzumab if EF <40% 1
• Treat anthracycline-induced cardiomyopathy with standard heart failure therapies including ACE inhibitors, beta-blockers (particularly carvedilol), digoxin, and diuretics 5
• Spironolactone may also be beneficial in managing anthracycline-induced cardiomyopathy 5

Understanding the cardiotoxic potential of various antineoplastic agents is crucial for appropriate cancer treatment planning and cardiac monitoring to minimize long-term cardiovascular morbidity and mortality.