A case report of 5-fluorouracil-induced coronary artery vasospasm.

Editor,

5-Fluorouracil (5-FU) is a chemotherapeutic agent, frequently used in the treatment of solid tumours, including colorectal, breast and upper gastrointestinal cancers. 5-FU can cause angina (effort-related or at rest)1, myocardial infarction, supraventricular and ventricular arrhythmias, acute pulmonary oedema, cardiogenic shock, cardiomyopathy, cardiac arrest, and sudden death, all recorded in association with intravenous (IV) infusion or bolus administration of the drug. We proceed to document a case of 5-Fluorouracil-induced coronary artery vasospasm.

Case History

A 76 year old gentleman diagnosed with adenocarcinoma of the low rectum and a coincidental left upper pole renal tumour, underwent abdomino-perineal excision of rectum (APER) and left nephrectomy. Pathology confirmed a PTla papillary variant renal cell carcinoma requiring no further treatment and a rectal adenocarcinoma staged ypT3NlM0, for which adjuvant 5-Fluorouracil and Folinic acid (5-FU/FA) chemotherapy was planned.

The past medical history included supraventricular tachyarrhythmia (on verapamil), hypertension and hypercholesterolaemia. The adjuvant chemotherapy schedule comprised the administration of four cycles of weekly IV bolus 5-FU/FA chemotherapy.

After his first dose of 5-FU, oncology notes confirmed one episode of chest pain, with a history suggestive of angina. After cycle 3 IV bolus of 5-FU, he was admitted under the medical team with a history of two episodes of exertional ‘aching’ central chest pain, each lasting one hour, over a 24 hour period. Troponin ‘T’ at twelve hours was elevated at 0.07μg/l. However, the medical team conferred a diagnosis of ‘atypical chest pain’ and he was subsequently discharged within 24 hours.

In view of his persistent complaint of chest pain, 5-FU was discontinued and he was switched to oral Capecitabine at 25% dose reduction. Despite this, a further admission to the medical team occurred following an episode of central crushing chest pain on the day following Capecitabine treatment. 12-lead ECG confirmed transient antero-lateral ST-segment elevation and/or hyperacute T waves on presentation to Casualty, (figure 2 and 3). Cessation of chest pain was noted with sublingual nitrate. Troponin ‘T’ at twelve hours was 0.06ug/l and he was transferred to the coronary care unit. He was initially managed as an acute coronary syndrome (ACS) with aspirin, clopidogrel and therapeutic enoxaparin. An oral beta-blocker was commenced and buccal suscard, (sublingual nitrate), added as required. He had no further episodes of chest pain whilst an inpatient. He proceeded to coronary angiography. Angiography revealed non-obstructive coronary artery disease, with a minimally diseased small diagonal branch of the LAD artery and a small RCA, with minimal disease distally. Verapamil (a rate-limiting calcium antagonist) was discontinued in view of the instigation of beta-blocker therapy and replaced by amlodipine. A long acting oral nitrate was commenced. Following an uncomplicated inpatient stay, the patient was discharged. Capecitabine was discontinued and he continues to attend Oncology for review. Capecitabine was not replaced by another agent. He has had no recurrence of chest pain off Capecitabine. He recently sustained a traumatic fractured neck of femur but is otherwise in good health to date.

Fig 2

12-lead Electrocardiogram demonstrating antero-lateral ST-segment elevation and/or hyperacute T wave changes.

Fig 3

12-lead Electrocardiogram showing normalised ST-segments/T waves after the administration of sublingual glyceryl trinitrate spray.

Discussion

5-FU is a chemotherapeutic agent used to treat many solid neoplasms. Cardiotoxicity, after 5-FU administration, has a reported incidence ranging from 1.27 to 18%2. The incidence of severe or life-threatening cardiotoxicity with 5-FU, i.e. the observation of electrocardiographic evidence of ST-segment elevation or the development of ventricular arrhythmias, appears to be much less frequent at 0.55%3.

Many suppositions have been proposed to elucidate the mechanism of 5-FU cardiotoxicity, including direct myocardial toxicity, coronary vasospasm, autoimmune phenomena, thrombogenic effect, and increased levels of endothelin4. The commonest hypothesis suggests that coronary artery vasospasm is induced by 5-FU. hi fact, in vitro studies propose that the activation of protein kinase C (PKC) modulates 5-FU-induced direct vasoconstriction of vascular smooth muscle5. Our patient's electrocardiogram demonstrated diffuse ST-segment elevation with hyperacute T wave changes, indicative of pervasive coronary artery vasospasm rather than isolated myocardial infarction secondary to a critical atherosclerotic lesion. This was supported by angiographic findings.

Clinical outcomes suggest that the vasospastic consequences of 5-FU are temporary and reversible. Support of the immediate discontinuation of 5-FU in the presence of cardiotoxicity has been advocated. Antivasospastic therapy should incorporate a full dose of calcium channel antagonist in addition to nitrate therapy.

In the majority of cases, 5-FU-induced cardiotoxicity is transient and reversible with supportive care. Nevertheless, in view of the potentially lethal profile seen with 5-FU cardiotoxicity and successful clinical outcomes associated with early detection and intervention, physicians should be aware of its existence.