According to the data from the Croatian Cancer Registry, pancreatic cancer was the eighth most common malignant tumor in men and the ninth in women in Croatia in 2013. It constitutes 3% of the total number of newly discovered malignant tumors. Adenocarcinomas make up 95% of all pancreatic cancers (1). Radical surgical resection is the only curative treatment method, reserved for a small number of patients with localized disease. Among those who undergo surgical resection, the 5-year survival rate is around 20%, with some indications that adjuvant treatment may impact this survival (2). For the majority of patients facing locally advanced or metastatic disease, available palliative options are confined to chemotherapy and radiation treatment. Current therapeutic strategies utilizing these methods in advanced disease have, at most, shown limited effectiveness.

Patients treated with combined modality therapy (CMT) after surgical resection have demonstrated improved survival compared to those undergoing surgery alone (3, 4). Neoadjuvant chemotherapy or chemoradiotherapy is recommended for patients with marginally resectable disease (2-4). The use of radiation therapy concurrently with 5-fluorouracil (5-FU) is an approach that has been widely adopted globally for the treatment of pancreatic adenocarcinoma. 5-fluorouracil (FU) is an antimetabolite effective against various neoplasms, such as breast, esophagus, larynx, gastrointestinal, and genitourinary cancers. Its nonselective cytotoxicity leads to systemic toxicity, most commonly causing neutropenia, stomatitis, and diarrhea (5).

Capecitabine, designed as a 5-FU prodrug, aims to enhance tolerability and intratumor drug concentrations by converting specifically to the active drug within tumors. Although patients may receive the drug orally in the convenience of their own homes, there are severe but rare adverse effects clinicians and patients should be aware of, including 5-FU-induced coronary vasospasm (6, 7). Herein, we present the case of a 74-year-old woman with pancreatic adenocarcinoma who presented to the hospital with capecitabine-induced acute coronary syndrome.

A 74-year-old woman was admitted to the Emergency Department because of a squeezing chest pain episode an hour before admission that lasted approximately 40 minutes, until she received 0.8 mg of sublingual nitroglycerine and 300 mg of aspirin. The patient reported she had vomited twice and sweated profusely. She had no prior history of cardiac disease, coagulation disorders, smoking, or drug abuse. Her BMI and lipid panel values were normal, and she was moderately physically active. The patient was only taking an angiotensin II receptor antagonist combined with a thiazide diuretic for arterial hypertension. The patient had undergone the Whipple procedure due to pancreatic adenocarcinoma two months ago. Treatment with oral capecitabine (2500 mg daily) was initiated 72 hours before admission.

The electrocardiogram (ECG) taken in the emergency room showed a sinus rhythm with a heart rate of about 73 beats per minute (bpm), with supraventricular premature beats and discrete ST segment depression in leads V5, V6, I, and avL. The patient had positive biochemical markers for myocardial ischemia (hs-cTnT 36.90 ng/L) and was transferred to the Coronary Intensive Care Unit (CICU). Urgent cardiac catheterization was performed and showed no coronary artery disease (CAD) (Figure 1). The echocardiogram, which was performed when the patient was pain-free, revealed normal left ventricular volume, slightly increased left ventricular wall thickness, no regional wall motion abnormalities with a left ventricular ejection fraction of 60%, grade I diastolic dysfunction, normal valve flow, and absence of pericardial effusion. The patient was initially treated with aspirin 100 mg, atorvastatin 80 mg, enoxaparin 5500 IU (40 mg) administered subcutaneously twice daily, glyceryltrinitrate 10 mcg/min via slow infusion, and diazepam 5 mg. During the next 24 hours, hs-cTnT levels were in decline, and consecutive ECG readings showed normalization of the ST segment. After two days, the patient was discharged from the hospital and diagnosed with myocardial infarction with non-obstructive coronary arteries (8) with solid suspicions of capecitabine-induced cardiac toxicity.

Thirty hours after discharge, the patient presented to the Emergency Department with the same symptoms arising two hours after taking 1000 mg of capecitabin. A new 12-lead ECG was immediately performed and revealed sinus tachycardia (110 bpm) with widespread ST-segment elevation (Figure 2), suggestive of global ischemia. Serum cardiac markers were again positive for myocardial ischemia (hs-cTnT 77.30 ng/L). The patient was transferred to the CICU and was given glyceryltrinitrate 10 mcg/min via slow infusion. The pain subsided shortly after parenteral nitrate infusion. A subsequent ECG performed 45 minutes afterward showed progressive recovery of ventricular repolarization abnormalities. Additionally, hs-cTnT values were declining. A team of cardiologists, gastroenterologists, and oncologists evaluated this case, and capecitabine treatment was ceased. The patient was carefully observed and released from the hospital after five days with trimetazidine 2x1, rosuvastatin 1x20 mg, isosorbide mononitrate 2x20 mg, and diazepam 5 mg. Gastroenterologists prescribed pancrelipase 3x25000 IJ with three main meals, ursodeoxycholic acid capsules 1x250 mg, high caloric oral nutritional supplement 1x daily, and otilonium bromide 3x40 mg. Oncologists ordered a control MSCT scan of the thorax, abdomen, and pelvis, which showed no signs of disease dissemination. The patient is currently receiving supportive and symptomatic treatment and is receiving regular check-ups with an oncologist.

Capecitabine may induce cardiotoxicity that can manifest as vasospasm, hypertension, ventricular arrhythmias, cardiogenic shock, and even cardiac arrest (6, 9), depending on cardiac comorbidity, dose, and the chemotherapy schedule (10). Capecitabine-induced cardiotoxicity is believed to result from the influence of 5-FU on the endothelium, leading to the production of endothelin-1 and subsequent coronary vasospasm (10). As a consequence, patients may exhibit symptoms resembling variant angina, including chest pain occurring even at rest. These symptoms can occur with or without ECG changes, indicating myocardial ischemia (11). In an American Heart Association (AHA) review of drugs associated with heart failure, Page et al. indicated that capecitabine is a known cardiotoxic drug (12). With regard to the onset of chest pain with capecitabine therapy, Wijesinghe et al. (13) reported an acute coronary syndrome in a patient who had been on capecitabine for only two days. Depending on the dose, cardiac side effects can occur within 24 hours after taking the drug (14). In a retrospective study by Jensen et al., symptoms were abolished by nitroglycerine (15). Our patient presented with chest pain three days after taking capecitabine for the first time and 2 hours after taking it the second time. The resolution of chest pain after using nitrates and normalization of ECG and hs-cTnT levels combined with the proven absence of CAD ruled out acute coronary syndrome in our patient.

This patient had capecitabine-induced coronary vasospasm without pre-existing CAD. Further use of capecitabine had to be discontinued to avoid the risk of cardiotoxicity. We emphasize the importance of adhering to the treatment plan, prevention of adverse effects, and promptly identifying any potential toxicities associated with this medication.