5-Fluorouracil–Induced Cardiotoxicity During Chemotherapy for Adenocarcinoma of the Small Bowel

CASE REPORT

A 57-year-old woman with a medical history of hypertension, type 2 diabetes mellitus, hyperlipidemia, and metastatic adenocarcinoma of the small bowel (Figure 1) receiving intravenous 5-fluorouracil (5-FU)–based chemotherapy developed three episodes of “pressure-like” chest pain radiating to the left arm. The first episode occurred while finishing her first cycle of 5-FU. An electrocardiogram (ECG) study performed during the chest pain episode showed nonspecific anterolateral ST-T changes (Figure 2). Results of serial cardiac enzyme analyses were normal. Pain resolved on nitroglycerin drip and IV morphine, and the ECG changes resolved an hour later (Figure 3).

Figure 1.

High-grade adenocarcinoma (circled) arising in a background of tubulovillous adenoma with muscularis propria and lymphatic invasion. Notice the irregular glands lined by pseudostratified columnar cells with hyperchromatic nuclei.

Figure 2.

ST segment and T wave changes in leads I, aVL, V1–V6

Figure 3.

Changes resolved

The second episode occurred a week later with the start of her second cycle of IV 5-FU. This time, the chest pain was more intense and associated with shortness of breath and diaphoresis. Electrocardiogram showed ST segment elevation in leads I and aVL, with hyperacute T waves in leads V1 thru V6 (Figure 4). Acute myocardial infarction (MI) was suspected. Serial cardiac enzymes were again normal. The patient was treated with IV metoprolol, nitroglycerin, and IV morphine. Her chest pain resolved, as did the ECG changes (Figure 5). The third episode of chest pain occurred on the day of discharge. Cardiac catheterization was performed and results were found to be within normal limits (Figures 6–10). A stress test (Figure 11) and myocardial SPECT (single photon emission computed tomography) scan were performed — the results of both were normal (Figures 12 and 13). A diagnosis of coronary vasospasm due to 5-FU was supported by the cardiac testing.

Figure 4.

ST segment elevations and T wave changes in leads I, aVL, V1–V6

Figure 5:

Changes resolved

Figure 6.

Left main coronary artery

Figure 10.

Right main coronary artery

Figure 11.

Pharmacological (adenosine) stress test showing no ischemic ST changes. Patient had no arrhythmias or chest pain and a stable blood pressure during the procedure.

Figure 12.

Myocardial perfusion scan. The images above are dynamic gated images that show no scarring and good wall motion. The calculated ejection fraction of the left ventricle was 76%.

Figure 13.

Myocardial perfusion scan (stress images). The images above show minimal nonspecific inferolateral adenosine-induced ischemia, which resolved at rest.

DISCUSSION

5-FU cardiotoxicity is a serious phenomenon that requires a high index of suspicion whenever the decision is made to use this drug as a treatment modality. It is associated with a broad spectrum of cardiovascular symptoms, such as arrhythmias, with and without cardiopulmonary symptoms. Adverse effects could even progress to acute MI symptoms, such as chest pain and shortness of breath with injury changes suggested on ECG, ventricular dysfunction, and, most serious of all, cardiogenic shock, cardiac arrest, and sudden death.^1,2 The incidence of 5-FU cardiotoxicity is 7.6%³ with mortality ranging between 2.2% and 13%.⁴

The most important risk factor is preexisting cardiac disease. Studies have shown that patients with a prior history of heart disease have a higher risk of 4.5% to 15.1% than patients without preexisting cardiac disease to develop cardiotoxicity.⁵ Higher doses of 5-FU bring a higher risk of toxicity.⁶ Studies suggest that bolus 5-FU therapy is associated with lower toxicity with a rate of 1.6% to 3% compared to continuous infusion 5-FU, which has a higher incidence of 7.6% to 18%. ⁵

The mechanisms by which 5-FU produces these cardiac side effects are unknown, but the one most often suggested is ischemia to the myocardium. Ischemia could be due to a direct toxic effect on the vascular endothelium involving NO synthase, which leads to coronary vasospasms. The other mechanism of vasospasm endothelial vasoconstriction is via protein kinase C.⁷ In a study of rabbits, one group was exposed to a single dose of 5-FU 50 mg/kg and the other group received repeated infusions of 15 mg/kg. The rabbits’ hearts were removed and analyzed shortly after death. The first group developed massive hemorrhagic MI with proximal coronary spasm and the second group developed left ventricular hypertrophy with foci of myocardial necrosis, thickening of myocardial arteries, and apoptosis of the endothelial cells of the distal coronary.⁸

Might a role exist for calcium channel blockers and nitrates in prophylaxis against cardiotoxicity? Some researchers maintain that prophylaxis will help, while others do not.^9,10 Dexrazoxane has been shown to be protective against 5-FU cardiotoxicity.¹¹ The management strategy most agreed upon is to monitor patients closely, discontinue treatment as soon as symptoms develop, and never administer the drug again to those patients who experience cardiotoxicity.^12,13 It is believed that 5-FU–induced cardiotoxicity is generally reversible. ¹⁴ Management of 5-FU–related cardiotoxicity, however, is not defined beyond discontinuing the drug. Some reports support the use of calcium channel blockers while others report no benefit.

Capecitabine, an oral prodrug of 5-FU, has been reported to cause cardiotoxicity as well, which has been demonstrated in a case report.¹⁵ Although it is suggested that the incidence of cardiotoxicity with capecitabine may be 1.5% to 2% lower than that of 5-FU, it is not advisable to administer capecitabine to patients with a history of 5-FU–induced cardiotoxicity.¹⁶

CONCLUSION

Our case report illustrates the clinical significance of 5-FU–induced cardiotoxicity. Physicians should retain a high degree of suspicion regarding these side effects when treating patients with 5-FU–based chemotherapy in order to prevent complications as early as possible. Thus, careful monitoring for cardiotoxicity is advised during the infusion of 5-FU. Finally, treatment with all fluoropyrimidines, including capecitabine, should be avoided in patients who have developed cardiotoxicity while undergoing treatment with 5-FU.

Figure 7.

Left main coronary artery

Figure 8.

Left main coronary artery

Figure 9.

Right main coronary artery