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https://doi.org/10.15836/ccar2024.236

Capecitabine-induced Acute Coronary Syndrome in a Patient with Pancreatic Adenocarcinoma

Karla Savić orcid id orcid.org/0000-0002-1339-8922 ; Opća bolnica Zadar, Zadar, Hrvatska
Mira Stipčević orcid id orcid.org/0000-0003-4351-1102 ; Opća bolnica Zadar, Zadar, Hrvatska
Jogen Patrk ; Opća bolnica Zadar, Zadar, Hrvatska
Dražen Zekanović orcid id orcid.org/0000-0002-8147-6574 ; Opća bolnica Zadar, Zadar, Hrvatska
Marin Bištirlić orcid id orcid.org/0000-0002-9213-4174 ; Opća bolnica Zadar, Zadar, Hrvatska


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Sažetak

Aim: To emphasize the severe adverse effects of capecitabine and prevent misdiagnosis
in patients with acute coronary syndrome. Methods: We present the case of a 74-year-old woman with
pancreatic adenocarcinoma who presented to the hospital with capecitabine-induced acute coronary
syndrome. She was admitted to the Emergency Department (ED) because of a squeezing chest pain
episode. Treatment with oral capecitabine (2500 mg daily) was initiated 72 hours before admission.
The patient had electrocardiographic (ECG) changes and positive biochemical markers for myocardial
ischemia (including HS-troponin T) and was transferred to the coronary intensive care unit. Urgent
cardiac catheterization was performed and showed no coronary artery disease (CAD). Thirty hours after
discharge, the patient presented to the ED with the same symptoms arising two hours after taking
1000 mg of capecitabine. The resolution of chest pain after using nitrates, normalization of ECG, and
HS troponin T levels combined with the proven absence of CAD ruled out acute coronary syndrome in
our patient. Conclusion: Our patient had capecitabine-induced coronary vasospasm in the absence of
pre-existing CAD. Further use of capecitabine had to be discontinued to avoid the risk of cardiotoxicity.

Ključne riječi

capecitabine; acute coronary syndrome; coronary vasospasm; cardiotoxicity; pancreatic cancer

Hrčak ID:

316849

URI

https://hrcak.srce.hr/316849

Datum izdavanja:

14.5.2024.

Podaci na drugim jezicima: hrvatski

Posjeta: 0 *




Introduction

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.

Case report

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.

FIGURE 1 Coronary angiography showing no obstructive coronary artery disease.
CC202419_5-6_236-40-f1

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.

FIGURE 2 An electrocardiogram suggesting global myocardial ischemia.
CC202419_5-6_236-40-f2

Discussion

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.

Conclusion

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.

LITERATURE

1 

Hrvatski zavod za javno zdravstvo. Bilten Incidencija raka u Hrvatskoj 2015. godine. Available from:https://www.hzjz.hr/wp-content/uploads/2018/03/Bilten_2015_rak_final.pdf (January 8, 2024)

2 

Crist DW, Sitzmann JV, Cameron JL. Improved hospital morbidity, mortality, and survival after the Whipple procedure. Ann Surg. 1987 September;206(3):358–65. https://doi.org/10.1097/00000658-198709000-00014 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/3632096

3 

Yeo CJ, Abrams RA, Grochow LB, Sohn TA, Ord SE, Hruban RH, et al. Pancreaticoduodenectomy for pancreatic adenocarcinoma: postoperative adjuvant chemoradiation improves survival. A prospective, single-institution experience. Ann Surg. 1997 May;225(5):621–33. https://doi.org/10.1097/00000658-199705000-00018 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/9193189

4 

Klinkenbijl JH, Jeekel J, Sahmoud T, van Pel R, Couvreur ML, Veenhof CH, et al. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Ann Surg. 1999 December;230(6):776–82. https://doi.org/10.1097/00000658-199912000-00006 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/10615932

5 

Walko CM, Lindley C. Capecitabine: a review. Clin Ther. 2005 January;27(1):23–44. https://doi.org/10.1016/j.clinthera.2005.01.005 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/15763604

6 

Polk A, Vistisen K, Vaage-Nilsen M, Nielsen DL. A systematic review of the pathophysiology of 5-fluorouracil-induced cardiotoxicity. BMC Pharmacol Toxicol. 2014 September 4;15:47. https://doi.org/10.1186/2050-6511-15-47 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/25186061

7 

Ang C, Kornbluth M, Thirlwell MP, Rajan RD. Capecitabine-induced cardiotoxicity: case report and review of the literature. Curr Oncol. 2010 February;17(1):59–63. https://doi.org/10.3747/co.v17i1.437 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/20179805

8 

Severino P, D’Amato A, Prosperi S, Myftari V, Colombo L, Tomarelli E, et al. Myocardial Infarction with Non-Obstructive Coronary Arteries (MINOCA): Focus on Coronary Microvascular Dysfunction and Genetic Susceptibility. J Clin Med. 2023 May 21;12(10):3586. https://doi.org/10.3390/jcm12103586 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/37240691

9 

Henry D, Rudzik F, Butts A, Mathew A. Capecitabine-Induced Coronary Vasospasm. Case Rep Oncol. 2016 October 17;9(3):629–32. https://doi.org/10.1159/000450544 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/27920693

10 

Südhoff T, Enderle MD, Pahlke M, Petz C, Teschendorf C, Graeven U, et al. 5-Fluorouracil induces arterial vasocontractions. Ann Oncol. 2004 April;15(4):661–4. https://doi.org/10.1093/annonc/mdh150 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/15033676

11 

Camaro C, Danse PW, Bosker HA. Acute chest pain in a patient treated with capecitabine. Neth Heart J. 2009 August;17(7-8):288–91. https://doi.org/10.1007/BF03086268 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/19789697

12 

Page RL 2nd, O’Bryant CL, Cheng D, Dow TJ, Ky B, Stein CM, et al. American Heart Association Clinical Pharmacology and Heart Failure and Transplantation Committees of the Council on Clinical Cardiology. Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular and Stroke Nursing; and Council on Quality of Care and Outcomes Research. Drugs That May Cause or Exacerbate Heart Failure: A Scientific Statement From the American Heart Association. Circulation. 2016 August 9;134(6):e32–69. https://doi.org/10.1161/CIR.0000000000000426 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/27400984

13 

Wijesinghe N, Thompson PI, McAlister H. Acute Coronary Syndrome Induced by Capecitabine Therapy. Heart Lung Circ. 2006 October;15(5):337–9. https://doi.org/10.1016/j.hlc.2006.03.010 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/16697705

14 

Schnetzler B, Popova N, Collao Lamb C, Sappino AP. Coronary spasm induced by capecitabine. Ann Oncol. 2001 May;12(5):723–4. https://doi.org/10.1023/A:1011152931300 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/11432636

15 

Jensen SA, Sørensen JB. Risk factors and prevention of cardiotoxicity induced by 5-fluorouracil or capecitabine. Cancer Chemother Pharmacol. 2006 October;58(4):487–93. https://doi.org/10.1007/s00280-005-0178-1 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/16418875


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