What is the risk of 5-Fluorouracil (5-FU) in patients with a prior history of coronary vasospasm?

Risk of 5-FU in Patients with Prior Coronary Vasospasm

Patients with a prior history of coronary vasospasm are at substantially elevated risk for recurrent and potentially life-threatening cardiac events when treated with 5-FU, and the drug should generally be avoided in favor of alternative chemotherapy regimens whenever oncologically feasible. 1

Magnitude of Risk

The risk profile for 5-FU-induced cardiac toxicity is particularly concerning in patients with pre-existing vasospastic disease:

• Pre-existing coronary artery disease substantially increases the risk of 5-FU cardiotoxicity, with one retrospective study showing coronary artery disease present in 38% of cardiotoxicity cases versus only 7% of controls (p < 0.05). 2

• The overall incidence of myocardial ischemia with 5-FU ranges from 1-18% depending on monitoring intensity, with silent ischemia detected in 6-7% of patients undergoing stress testing. 1, 3

• Coronary vasospasm is a primary mechanism of 5-FU cardiotoxicity, with persistent spasm documented during cardiac catheterization in patients receiving continuous infusion. 1, 3, 4

Pathophysiologic Mechanisms

Understanding why patients with prior vasospasm are at heightened risk:

• 5-FU induces endothelium-independent vasoconstriction through protein kinase C-mediated mechanisms in vascular smooth muscle, which can occur at the site of pre-existing plaques. 1

• Direct endothelial injury leads to microthrombotic occlusions that are undetectable by coronary angiography but represent key ultrastructural findings. 1, 3

• Cardiac events typically manifest within 2-5 days after initiation of 5-FU therapy, with symptoms usually lasting up to 48 hours. 3

Clinical Management Algorithm

Pre-Treatment Assessment

• Ischemic workup should be initiated in all high-risk patients (including those with prior vasospasm) before administration of 5-FU. 1

• Serial ECGs should be obtained during 5-FU administration with frequent vital signs monitoring during infusion. 3

If 5-FU Must Be Used

The preferred approach is prophylactic cardioprotective therapy rather than re-challenge without protection:

• Preemptive use of coronary vasodilators (nitrates and calcium-channel blockers) should be considered before each 5-FU administration. 1, 3

• A 2022 retrospective study of 78 patients with prior 5-FU vasospasm showed that pre-treatment with calcium channel blockers and/or nitrates allowed safe re-challenge, with chest pain recurring in only 19.2% (without myocardial infarction) versus 66.7% in those without pre-treatment (p = 0.048). 5

• No difference in efficacy was found between single-agent (nitrates or CCBs alone) versus combination therapy for preventing recurrent vasospasm (14.7% vs. 25.0%, p = 0.26). 5

• Patients who continued 5-FU after cardioprotective pre-treatment had decreased risk of death (HR 0.42, p = 0.005) compared to those who stopped 5-FU entirely. 5

If Cardiac Symptoms Develop

• Offending drugs should be withheld immediately until diagnostic workup is completed and anti-anginal therapy is instituted. 1

• Patients with suspected acute coronary syndrome should be treated according to ACC/AHA guidelines, including consideration of percutaneous coronary intervention despite thrombocytopenia concerns. 1, 3

• Parenteral diltiazem is an effective and safe approach for acute treatment of coronary vasospasm secondary to 5-FU infusion. 6

Long-Term Strategy

• Alternative regimens that do not contain 5-FU are a better option than re-challenge, even with cardioprotective pre-treatment. 1, 3

• Temporary or permanent discontinuation of 5-FU is advised in patients developing cardiac ischemia during or following treatment. 1

Critical Pitfalls to Avoid

• Do not assume normal coronary angiography excludes 5-FU cardiotoxicity, as endothelial injury and small vessel thrombosis may be undetectable by angiography. 1, 7

• Do not underestimate the clinical problem, as silent ischemia may be more prevalent than symptomatic cases, and sudden cardiac death has been reported. 1, 3

• Do not deny life-saving interventions due to chemotherapy-induced thrombocytopenia, as aspirin and antiplatelet therapy can be used safely with appropriate platelet count thresholds. 1

• Recognize that cardiotoxicity can be completely reversible after rapid cessation of therapy, but readministration without protection may lead to serious cardiac damage or death. 7