Cardiotoxicity of 5-Fluorouracil

Abstract

Cardiac side effects of the cytostatic agent 5-fluorouracil (5-FU) have an incidence of 1.2-7.6%. Potentially, arrhythmias, myocardial infarction and sudden cardiac death could occur. Life-threatening cardiotoxicity is rarely observed with a frequency <1%. Cardiotoxicity of 5-FU seems to differ from well known effects of other cytostatics, e.g., anthracyclines. Myocardial ischemia was suggested as potential mechanism due to occasionally observed ECG alterations during 5-FU administration. Experimental studies revealed potential mechanisms of cardiotoxicity ranging from direct toxic effects on vascular endothelium involving endothelial NO synthase leading to coronary spasms and endothelium independent vasoconstriction via protein kinase C. In addition, rheological side effects have to be considered. Coronary artery disease is judged to increase the risk of cardiac side effects. Despite lack of prospective trials, verapamil type calcium antagonists as well as nitrates seem to be useful for treatment of 5-FU induced coronary spasms. In addition, modification of the cytostatic regimen has to be considered in patients who had been symptomatic. It could be assumed that 5-FU toxicity is reversible in the majority of cases when acute complications, e.g., arrhythmias, are resolved.

Cardio-Oncology

“…90 Common antimetabolites include 5-fluorouricil (5-FU), capecitabine, cytarabine, gemcitabine, methotrexate, and hydroxyurea, which are commonly used to treat leukemia, ovarian, breast, gastrointestinal, and other solid tumors. Fluorouracil is widely used antimetabolite, with an incidence of cardiotoxicity ranging from 1% to 7.6%.…”

“…Fluorouracil is widely used antimetabolite, with an incidence of cardiotoxicity ranging from 1% to 7.6%. 90 The most commonly described cardiac effects are myocardial ischemia, angina, chest pain, and ECG changes (ST-segment changes and T-wave abnormalities; Figure 1). The incidence of ischemia related to 5-FU is higher in patients with underlying coronary disease (4.5%) compared with patients without known disease (1.1%).…”

Peripheral arterial ischemic events in cancer patients

“…In general, mechanisms for these events have included chemotherapyinduced expression of macrophagemonocyte tissue factor, 64 endogenous procoagulantanticoagulant mismatch, 65,66 accentuated tumor and endothelial cell death, and cytokine release resulting in increased expression of tissue factor 67,68 and enhanced endothelial cell reactivity to platelets. 69 Certain chemotherapy agents (Table 3) have been associ ated with arterial thromboembolic events more than others: 5fluorouracil can decrease protein C levels and increase fibrinopeptide A levels 70 besides leading to endothelial damage and even endothelialindependent vasoconstriction via protein kinase C. 71 Gemcitabine has been associated with vascular events ranging from digital ischemia, VTE, thrombotic microangiopathy and systemic capillary leaks. 72 Cisplatin, a central component of several chemotherapeutic regimens, induces thrombosis by causing endothelial dam age, 73 activating platelets 74 and increasing monocyte tissue factor activity, 64 with a 12-17.6% risk 75 of strokes, recurrent peripheral arterial thromboembolic events and/or aortic thrombosis ( Figure 6).…”

Successful Treatment with Modified FOLFOX6 and Panitumumab in a Cecal Cancer Patient Undergoing Hemodialysis

“…Cardiac toxicities are also rare, however, significant complications are associated with 5-FU therapy and EGFR monoclonal antibodies (14). 5-FU associated cardiotoxicity is reported in 1.2-7.6% of patients (15). A Japanese postmarketing survey of panitumumab revealed that cause-unidentified death occurred in 0.03% (1/3,085), death caused by cardiac failure occurred in 0.03% (1/3,085) and cardiac disorders occurred in 0.23% (7/ 3,085) of patients (16).…”