What are the recommendations for monitoring and managing cardiac toxicity in patients with pre-existing heart conditions undergoing chemotherapy with anthracyclines (e.g. doxorubicin) or trastuzumab?

Monitoring and Managing Cardiac Toxicity in Patients with Pre-existing Heart Conditions on Anthracyclines and Trastuzumab

Patients with pre-existing heart conditions receiving anthracyclines or trastuzumab require baseline LVEF assessment followed by serial monitoring at 3,6, and 9 months during treatment, then at 12 and 18 months post-initiation, with immediate treatment discontinuation if LVEF falls below 40% and initiation of ACE inhibitors plus beta-blockers for any detected left ventricular dysfunction. 1

Pre-Treatment Risk Assessment and Optimization

Before initiating cardiotoxic chemotherapy, comprehensive cardiovascular evaluation is mandatory 2:

• Measure baseline LVEF using echocardiography or MUGA scan to establish reference values for serial monitoring 3
• Obtain global longitudinal strain (GLS) imaging at baseline when available, as decreased baseline GLS ≥-18% independently predicts cardiotoxicity even with normal LVEF 2
• Measure cardiac biomarkers (troponin I or T and BNP/NT-proBNP) in all high-risk patients with pre-existing cardiovascular disease 2
• Optimize pre-existing cardiac conditions with beta-blockers and ACE inhibitors where appropriate, maximize medical therapy for coronary artery disease, and consider revascularization if clinically indicated 1

Serial Monitoring Schedule During Treatment

The monitoring frequency differs based on treatment setting and agent 1:

For Adjuvant Anthracycline/Trastuzumab Therapy:

• Baseline, 3,6, and 9 months during treatment
• 12 and 18 months after treatment initiation
• Increased vigilance for patients ≥60 years old throughout treatment 1

For Anthracyclines Specifically:

• After cumulative doxorubicin dose of 250 mg/m² (or epirubicin 450 mg/m², mitoxantrone 60 mg/m²) 2
• After each additional 100 mg/m² of doxorubicin beyond 250 mg/m² 2

For Metastatic Disease:

• Baseline LVEF with infrequent monitoring in the absence of symptoms 1

Cardiac Biomarker Monitoring:

• Troponin I or T and BNP/NT-proBNP every 3-6 weeks or before each chemotherapy cycle using the same institutional laboratory 2
• Troponin peaks at approximately 96 days after starting anthracyclines, making this the optimal time for maximal troponin assessment 4

Critical LVEF Thresholds and Treatment Decisions

During Anthracycline Treatment 1:

LVEF reduction ≥15% from baseline with LVEF ≥50%:

• Continue anthracyclines with close monitoring 1

LVEF decline to <50%:

• Reassess after 3 weeks
• If confirmed: hold chemotherapy, consider therapy for left ventricular dysfunction, perform frequent echocardiographic checks 1

LVEF decline to <40%:

• Stop chemotherapy immediately
• Discuss alternative treatments
• Initiate heart failure therapy with ACE inhibitors plus beta-blockers 1

During Trastuzumab Treatment (Post-Anthracyclines) 1:

LVEF decline to <50%:

• Reassess after 3 weeks
• If confirmed: continue trastuzumab, consider therapy for left ventricular dysfunction, perform frequent echocardiographic checks 1

LVEF decline to <40%:

• Stop trastuzumab immediately
• Treat left ventricular dysfunction 1

The FDA label for trastuzumab specifies withholding treatment for ≥16% absolute decrease in LVEF from pre-treatment values OR LVEF below institutional limits of normal with ≥10% absolute decrease 3

Pharmacologic Management of Detected Cardiotoxicity

All patients with symptomatic left ventricular dysfunction and LVEF <40% must be treated with an ACE inhibitor in combination with a beta-blocker unless specific contraindications exist 1

Critical timing considerations 1:

• Initiate ACE inhibitors and beta-blockers within 2 months from the end of anthracycline therapy for patients showing left ventricular dysfunction, even if asymptomatic 1
• Earlier heart failure therapy initiation (within 2 months) results in better therapeutic response 1

For patients with subclinical cardiotoxicity identified by elevated troponin, treatment with ACE inhibitors (enalapril) may prevent LVEF reduction and associated cardiac events 1

Cardioprotective Strategies for High-Risk Patients

For patients at high risk of cardiotoxicity, consider 1:

• Liposome-encapsulated doxorubicin to minimize cardiotoxicity 1
• Dexrazoxane as a cardioprotectant, though the American Society of Clinical Oncology recommends this only for patients with metastatic breast cancer who have already received more than 300 mg/m² of doxorubicin 1
• Beta-blockers, ACE inhibitors, or AT1-antagonists as part of a cardioprotectant regimen 1

Advanced Imaging Parameters for Early Detection

Beyond LVEF monitoring, additional parameters improve early detection 2, 4:

• Left ventricular end-systolic volume (LVESV) at 1 month post-anthracycline treatment is an early detector of cardiotoxicity, with higher values (40 mL vs. 29.5 mL) predicting subsequent dysfunction 4
• Global longitudinal strain (GLS) at 1 month post-anthracycline shows more pronounced decline in those who develop cardiotoxicity (-17.6% vs. -21.4%) 4
• Baseline LVEF is an independent predictor of later cardiotoxicity 4

Long-Term Surveillance Requirements

Post-treatment monitoring is essential 1, 2:

• Follow-up echocardiography at 3,6, and 12 months after completion of anthracycline therapy, even in asymptomatic patients 2
• Long-term surveillance at 4 and 10 years after anthracycline therapy for patients treated at age <15 years OR those receiving cumulative doxorubicin >240 mg/m² or epirubicin >360 mg/m² 1, 2
• LVEF measurements every 6 months for at least 2 years following completion of trastuzumab as adjuvant therapy 3

Critical Pitfalls to Avoid

Do not wait for symptomatic heart failure before intervention - LVEF measurement is relatively insensitive and only detects changes after significant myocardial damage has occurred 1, 5

Recognize that trastuzumab cardiotoxicity differs from anthracycline toxicity - it is potentially reversible (Type II cardiotoxicity) and patients who develop cardiac dysfunction during trastuzumab alone (without prior anthracyclines) can be observed if they remain asymptomatic and LVEF remains ≥40% 1

Avoid anthracycline-based therapy for up to 7 months after stopping trastuzumab due to the long washout period and increased risk of cardiac dysfunction 3

Monitor pregnant women or those who become pregnant within 7 months of trastuzumab for oligohydramnios, as trastuzumab can cause fetal harm 3