What are the cardiac side effects of 5-Fluorouracil (5-FU)?

Cardiac Side Effects of 5-Fluorouracil (5-FU)

5-FU causes myocardial ischemia as its primary cardiac toxicity, manifesting most commonly as chest pain in up to 18% of patients, with the mechanism involving coronary vasospasm and endothelial injury. 1

Primary Cardiac Manifestations

Ischemic Events (Most Common)

• Chest pain is the most frequent cardiac symptom, occurring in 1-68% of patients depending on the study population and monitoring intensity 1
• Myocardial infarction occurs in approximately 22% of cardiac events 2
• Ischemic ECG changes are documented in 68% of patients experiencing cardiac events 1
• Cardiac biomarker elevations occur in 43% of cases with ischemic changes 1
• Silent myocardial ischemia has been detected in 6-7% of patients when stress testing is performed, suggesting clinical underestimation of the problem 1, 3

Severe Complications (Less Common)

• Arrhythmias can occur as a secondary manifestation 1
• Heart failure is a recognized but less common side effect 1
• Cardiogenic shock occurs in approximately 1% of cardiac events 1, 2
• Sudden cardiac death has been reported 1
• Overall mortality from 5-FU cardiotoxicity ranges from 2.2% to 13% 1

Risk Factors for Cardiotoxicity

Dose and Administration-Related

• High-dose 5-FU (>800 mg/m²) carries significantly higher risk 1
• Continuous infusion has a cardiotoxicity rate of 7.6% compared to 2% with bolus injections 1
• Continuous infusion for 24 hours over 5 days, especially with leucovorin, shows the highest toxicity rates 4

Patient-Related Risk Factors

• Pre-existing cardiovascular disease substantially increases risk 1
• Prior mediastinal radiation accelerates drug-related coronary damage 1
• Concurrent use of other chemotherapeutic agents increases cardiotoxicity 1

Temporal Pattern and Pathophysiology

Timing of Events

• Cardiac events typically manifest within 2 to 5 days after initiation of 5-FU 1
• Symptoms are usually short-lasting (up to 48 hours) 1
• Chest pain and ischemic ECG changes typically occur at rest rather than during exercise 1, 3
• Symptoms sometimes persist even after treatment cessation 1, 3

Mechanisms of Cardiotoxicity

• Coronary vasospasm is a primary mechanism, with persistent spasm observed during cardiac catheterization 1
• Endothelial injury leads to microthrombotic occlusions undetectable by angiography 1
• Direct toxicity on myocardium contributes to the overall effect 1
• Protein kinase C-mediated vasoconstriction of vascular smooth muscle has been demonstrated experimentally 1

Clinical Management Approach

Monitoring Requirements

• Serial ECGs should be obtained during 5-FU administration 1
• Frequent vital signs monitoring is recommended during infusion 1
• Patients should be informed about cardiac symptoms and instructed to report them immediately 5
• Close cardiac monitoring is the most established method to prevent manifest cardiotoxic events 2

Acute Management

• Immediately withhold 5-FU if chest pain or cardiac symptoms develop 1
• Complete diagnostic workup before considering re-challenge 1
• Institute anti-anginal therapy with nitrates and calcium-channel blockers 1, 3
• Patients with suspected acute coronary syndrome should be treated according to ACC/AHA guidelines 1

Treatment Decisions

• Alternative regimens not containing 5-FU are preferred over re-challenge 1
• Re-challenge is possible with close monitoring but carries risk 1
• Preemptive use of coronary vasodilators (nitrates and calcium-channel blockers) should be considered 1, 3

Important Clinical Caveats

The problem of 5-FU cardiotoxicity is likely clinically underestimated, particularly in patients without cardiac history who are treated as outpatients without cardiac monitoring 2. Asymptomatic and symptomatic cardiac events may be overlooked in these settings 2.

Capecitabine (oral prodrug of 5-FU) has lower but still significant cardiotoxicity (3-9%) due to preferential activation in cancer cells 1. However, it still causes symptomatic ischemic ECG changes in 5.2% of patients without prior coronary disease 1.

Coronary angiography may appear normal despite severe symptoms, as the mechanism involves vasospasm and microvascular injury rather than fixed coronary stenosis 6. This can lead to underdiagnosis if clinicians rely solely on angiographic findings.