Clinical Geriatrics

Introduction
5-fluorouracil (5-FU) capecitabine is the cornerstone of chemotherapy in patients with gastrointestinal cancers, colon cancer, head and neck cancer, or breast and pancreatic cancer. The widespread use of this drug has increased the incidence of drug-related cardiotoxicity. 5-FU and related agents can cause cardiac stunning, defined as the short, persistent defect in the contractility of myocardium, which reverses by itself with time once the initial insult is over. Advancing age is a risk factor for the development of drug-related cardiotoxicity, and as the elderly population increases, older adults will have increased potential for exposure to 5-FU. It is important for physicians to consider the possibility of cardiotoxicity in elderly patients undergoing 5-FU chemotherapy for various cancers.

Case Presentation
A 61-year-old male with history of hypertension and hypercholesterolemia presented with iron deficiency anemia (hemoglobin, 6.8 g/dL). Upper endoscopy (EGD) revealed Helicobacter pylori infection, which was treated successfully. He continued to be anemic and required intravenous iron therapy. His EGD was followed by small-bowel video capsule endoscopy. The capsule was retained, and a subsequent kidney/ureter/bladder x-ray of the abdomen revealed a metallic object in the lower left quadrant. The patient underwent laparotomy, showing matted small intestine with innumerable nodules on the visceral peritoneum. Biopsy showed small-bowel adenocarcinoma, stage T4 N0. Gene expression profile testing confirmed the colorectal origin of the malignancy.

The patient underwent segmental resection of the small intestine with reanastomosis. Chemotherapy with FOLFOX (folinic acid, 5-FU, oxaliplatin) and bevacizumab was planned. Within 24 hours of administering the first dose of 5-FU intraperitoneally, the patient complained of severe chest pain lasting for 20 hours associated with dyspnea. The chest pain was subclavicular in location on both sides and without any radiation. Computerized tomography scan of the chest with contrast ruled out pulmonary embolism. Electrocardiogram (EKG) showed sinus rhythm, heart rate of 85 bpm, left axis deviation with prolonged QT interval, but essentially negative for any ST-T wave changes. However, serial troponins increased from 0.037 ng/mL to 0.124 ng/mL. Echocardiogram was significant for severely reduced left ventricular systolic function with ejection fraction of 15-20% and a normal right ventricle. Non-ST segment elevation myocardial infarction (NSTEMI) was considered, and the patient underwent cardiac catheterization.

Coronary angiography did not reveal any occlusion. Acute nonischemic cardiomyopathy secondary to 5-FU was diagnosed. The chemotherapy was discontinued, and the patient’s cardiomyopathy was treated with aspirin and beta blockers. By the fifth hospital day, he was completely symptom-free, and a follow-up echocardiogram showed improving systolic function with ejection fraction of 40-50%. The patient was discharged home on the sixth day of admission to follow up with a cardiologist in one month for follow-up echocardiogram.

Discussion
Cardiac stunning due to 5-FU is not well-defined. 5-FU tends to cause alteration in cardiac contractility, which resolves over time with discontinuation of the drug. This is thought to be a result of momentary ischemia to the myocardium followed by reperfusion, which is mediated by endothelial, myocyte, neural, or free radical mechanisms,¹ modulating the amount of blood flow to a specific region of the myocardium.

Nonischemic cardiomyopathy due to 5-FU treatment is an uncommon but observed phenomenon. Different studies have shown a wide range of incidence and mortality from this phenomenon.