Managing life-threatening 5-fluorouracil cardiotoxicity
- 1 Department of Internal Medicine, University of Florida Health at Jacksonville, Jacksonville, Florida, USA
- 2 Department of Cardiology, University of Florida Health at Jacksonville, Jacksonville, Florida, USA
- 3 Department of Hematology/Oncology, University of Florida Health at Jacksonville, Jacksonville, Florida, USA
- Correspondence to Dr Kimberly Boldig; kimberly.boldig@jax.ufl.edu
Abstract
5-Fluorouracil (5-FU), a known cardiotoxin, is the backbone for the treatment of colorectal cancer. It is associated with arrhythmias, myocardial infarction and sudden cardiac death. Most commonly, it is associated with coronary vasospasm secondary to direct toxic effects on vascular endothelium.
A woman with metastatic colon cancer, originally treated with a 5-FU infusion as part of the FOLFIRI (Folinic acid, 5-Fluorouracil, Irinotecan) regimen, was unable to tolerate the chemotherapy due to chest pain. She was transitioned from infusional 5-FU to inferior 1-hour bolus 5-FU, in an attempt to minimise cardiotoxicity, but had disease progression. A multidisciplinary decision was made to again trial 5-FU infusion and pretreat with diltiazem. She tolerated chemotherapy without adverse events. A multidisciplinary discussion is recommended for co-management of reversible 5-FU-associated cardiotoxicity. After coronary artery disease (CAD) risk stratification and treatment, empiric treatment with calcium channel blockers and/or nitrates may allow patients with suspected coronary vasospasm, from 5-FU, to continue this vital chemotherapy.
Background
Knowledge of chemotherapies and their resultant side effect profiles and toxicities continues to evolve. An understanding of these elements is essential to providing targeted cancer treatment while allowing for better patient tolerance. The possibility of cardiac toxicity with some chemotherapy regimens has been well documented in the literature. Some of the most notable cardiotoxic chemotherapies include anthracyclines and 5-fluorouracil (5-FU). 5-FU is a crucial component of several chemotherapy regimens. It is the third most used chemotherapy agent for treatment of solid malignancies and is the second most common drug associated with cardiotoxicity.1 2 The most common symptom experienced by its users is chest pain. However, other side effects include atypical chest pain, angina, acute coronary syndromes (ACSs), arrhythmias, myocarditis, pericarditis and heart failure.2 3 Cancer causes a proinflammatory and hypercoagulable state, which may increase cardiovascular risk in these patients.4 Cardiotoxic chemotherapy may further increase this risk. Objective evidence of cardiotoxicity has also been seen through ECG monitoring. Electrocardiographic testing may demonstrate diffuse ST segment elevation or depression, tall-peaked T waves, T wave inversions, sinus tachycardia, prolongation of the QT interval, atrial fibrillation, ventricular extrasystoles, sustained and non-sustained ventricular tachycardia, and ventricular fibrillation.5–8 2%–7% of patients treated with 5-FU experience side effects.5–9 The timing of cardiac symptoms following 5-FU administration is variable. Symptoms may develop immediately after infusion or up to 2 days after the medication has been administered. The correlation between 5-FU and cardiotoxicity is well known; however, the mechanism behind it is not. Because this pathogenesis is not well understood, proposed treatment options have been contradictory and, many times, detrimental to effective cancer treatment.
Until recently, the recommended treatment for 5-FU cardiotoxicity was to discontinue the infusion and replace 5-FU with a different chemotherapy agent.5 9 10 5-FU re-challenge has been associated with myocardial infarction and a 13% mortality.11 12 However, changing chemotherapy regimens may also be detrimental to the patient because it usually leads to administering inferior treatment. This leads to a treatment dilemma between balancing cardiotoxic effects of chemotherapy and risk of possible progression of disease.
Treatment options have been proposed to prevent the cardiotoxic side effects associated with 5-FU. Some sources recommend prophylactic treatment with a calcium channel blocker and nitrate.4 9 One study found pretreatment with two calcium channel blockers, and a long-acting nitrate allowed for successful re-challenge with fluoropyrimidine treatment for 11 patients.2 Another case report described a patient who developed ventricular fibrillation following FOLFOX (Folinic acid, 5-Fluorouracil, oxaliplatin) chemotherapy infusion. This patient was found to have ST elevation with a negative coronary angiogram for thrombo-occlusive disease. The patient was successfully pretreated with isosorbide dinitrate, diltiazem and metoprolol to allow continued chemotherapy treatment with 5-FU.13 A case series for the oral 5-FU prodrug, capecitabine, found that prophylaxis with diltiazem allowed for continued treatment with the desired chemotherapy regimen.14 The effectiveness of this treatment has also been contradicted. Opposing literature reports pretreatment with calcium channel blockers failed to prevent recurrence of cardiotoxicity.4 8 15 This demonstrates the importance of further understanding of the mechanism behind the pathogenesis of 5-FU cardiotoxicity and continued research behind treatment options.
Our case report demonstrates successful treatment of 5-FU cardiotoxicity with diltiazem, allowing continued chemotherapy treatment.
Case presentation
Our patient presented to our institution with metastatic colon cancer. She was originally treated with a 5-FU infusion, as part of the FOLFIRI regimen, and subsequently developed chest pain. She described chest pain that radiated to her neck and shoulder and occurred at rest. Her presentation was concerning for an ACS. Differential diagnoses included 5-FU-induced toxicity causing vasospasm, ventricular arrhythmia, cardiomyopathy, myocarditis or pericarditis. Additionally, other explanations of sudden chest pain include pulmonary embolus, gastroesophageal reflux disease(GERD), panic disorder or a musculoskeletal origin such as costochondritis.
Cardiology completed an evaluation. ECG demonstrated normal sinus rhythm, and troponins were within normal limits. A chest X-ray was completed and found no acute cardiopulmonary process. The normal ECG, troponins and chest X-ray helped to rule out arrhythmia, myocarditis and pericarditis. However, the treatment team was aware that an arrhythmia could have occurred during 5-FU infusion and was missed on subsequent ECGs. Stress test was performed and showed no inducible ischaemia. Echocardiogram demonstrated a normal ejection fraction without any regional wall motion abnormalities, ruling out hypokinesis, cardiomyopathy or cardiogenic shock. This workup helped to rule out ACS as the cause for chest pain. A CT pulmonary angiogram was performed, and no pulmonary embolus was identified. Although the cardiology workup was thorough and unremarkable, the patient elected not to continue with 5-FU infusion.
The patient was then treated with 5-FU bolus-leucovorin-irinotecan and subsequently 5-FU bolus-leucovorin chemotherapy regimens. Both regimens were stopped because of adverse effects and, ultimately, disease progression. Because the patient had resolution of symptoms after changing the chemotherapy regimen, this indicated GERD, panic disorder and costochondritis were likely not the cause of chest pain. The differential was narrowed to 5-FU-induced coronary vasospasm. The decision was made to start coronary vasospasm prophylaxis with a calcium channel blocker, diltiazem extended release (ER) 240 mg. The prophylaxis was given prior to retrial of 5-FU infusion, under close cardiology monitoring. For the first cycle, the patient was admitted to the hospital and monitored on telemetry. The patient tolerated the 48-hour chemotherapy infusion without angina. Telemetry showed no abnormal rhythms during infusion. The post-treatment ECG was unchanged from pretreatment, demonstrating normal sinus rhythm. The post-treatment echocardiogram was also unchanged with normal ejection fraction.
Outcome and follow-up
The patient completed subsequent cycles of chemotherapy with diltiazem ER 240 mg pretreatment as an outpatient, without extensive cardiac monitoring, and continued to tolerate the treatment.
Discussion
Risk factors that are thought to be related to 5-FU cardiotoxicity include those that increase risk for coronary artery disease. In addition, factors such as frequency of administration and polychemotherapy are also believed to play a role.1 Pre-existing cardiovascular disease has not been correlated with increased risk of cardiotoxicity.2 However, other suspected risk factors include smoking, diabetes, hypercholesterolaemia, family history of heart disease, and previous or concomitant radiation therapy.1 3 4 Many times, the myocardial injury caused by fluoropyrimidines may be seen as ECG changes and elevated myocardial biomarkers. Once the patient receives angiography or stress echocardiogram, it is usually without coronary artery stenosis.1 2 4 14 Infusion and bolus dosing of 5-FU are associated with similar rates of adverse cardiac events.1 Labianca et al studied the correlation of 5-FU cardiotoxicity as a monotherapy regimen versus combination therapy with other possible cardiotoxic chemotherapy medications. They found no statistically significant difference between the two groups.10 Additional cardiotoxic chemotherapy that may be used in the treatment of colorectal cancer include: bevacizumab, cetuximab, panitumumab, regorafenib and aflibercept.16 None of which were used in our patient.
Various mechanisms have been proposed as the possible pathophysiology behind 5-FU-induced cardiotoxicity. Some hypotheses include vasospasm, thrombi formation and cellular apoptosis (figure 1). The most frequently proposed mechanism is 5-FU-induced coronary vasospasm.2 4 9 14 15 Many studies have evaluated patients with 5-FU cardiotoxicity via coronary angiography which failed to identify significant coronary artery disease, further supporting the likelihood of 5-FU-induced vasospasm.2 4 14 The mechanism is believed to be related to endothelial dysfunction. Normally, when blood flow increases through a vessel, vasodilatory agents such as acetylcholine are released. Acetylcholine causes the release of nitric oxide (NO) from endothelial cells. This occurs by upregulating calcium release which binds calmodulin and activates endothelial NO synthase. NO causes relaxation of smooth muscle lining of the endothelium via the cyclic-guanosine monophosphate pathway.4 9 15 17 Endothelial cell damage, or toxic effects of 5-FU on endothelium, may interfere with these mechanisms, causing vasoconstriction. 5-FU may also cause vasospasm by potentiating signaling molecules that cause vasoconstriction. These proteins are believed to include endothelin and protein kinase C. Endothelin is a vasoconstrictor and has been found to be elevated in patients treated with 5-FU.2 4 5-FU is also believed to potentiate the vasoconstrictor effects of protein kinase C.4 9 15 The process behind 5-FU-induced vasospasm is still unknown, but inhibition of the NO pathway and potentiation of vasoconstrictor molecules are two possible mechanisms by which it may occur.
Flow chart demonstrating the mechanisms of 5-fluorouracil (5-FU) cardiotoxicity. The blue boxes in the chart represent the main categories of cardiac endothelial involvement. The green boxes represent the mechanism of each corresponding component of cardiotoxicity. The red stop arrow (left column) indicates a mechanism that is proposed to be inhibited by 5-FU.
5-FU has been proposed to cause thrombi formation, possibly leading to cell injury or death. Endothelial dysfunction caused by 5-FU may promote platelet and fibrin formation, leading to an occlusive thrombus.2 5-FU has been described as directly toxic to the endothelium of coronary arteries, causing intima disruption, denudation, subsequent platelet accumulation and fibrin formation. This effect was mitigated by concurrent treatment with antithrombotic medications.1 9 18
Cardiotoxicity associated with 5-FU may also be associated with it's mechanism for causing apoptosis. This mechanism is helpful to treat cancer cells but may contribute to deleterious effects in cardiac tissue. Although the mechanism for 5-FU-induced apoptosis is not well understood, it is believed that cell death occurs through formation of reactive oxygen species (ROS).19 5-FU may cause mitochondrial uncoupling and hypoxic cell injury leading to increased levels of ROS and decreased antioxidant agents. Cardiomyocytes, when exposed to 5-FU, may require increased oxygen consumption, increased ROS production and cellular hypoxia.2
Our literature review identified various potential mechanisms of 5-FU cardiotoxicity. Our case identifies successful reinitiated chemotherapy treatment with 5-FU after pretreatment with diltiazem. Diltiazem is a non-dihydropyridine calcium channel blocker that inhibits the inflow of calcium ions during depolarization. When this mechanism is blocked, it increases smooth muscle relaxation and coronary artery dilation.20 Diltiazem targets the proposed mechanism of 5-FU-induced vasospasm. Successful pretreatment in our patient without continued 5-FU adverse effects increased the likelihood that at least some component of 5-FU cardiotoxicity relates to its propensity to cause vasospasm.
Our case report also identifies other mechanisms that may be targeted concurrently to prevent 5-FU cardiotoxicity and may even further enhance tolerability. Management of 5-FU-induced cardiotoxicity should include obtaining use of serial use of ECG and cardiac biomarkers while and ruling out ACS. Continued chemotherapy treatment may be desirable and attainable with pretreatment with diltiazem.
Learning points
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5-Fluorouracil (5-FU) is a component of many chemotherapy regimens but also has known cardiotoxicity.
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The mechanism behind 5-FU cardiac toxicity is not well understood, but proposed mechanisms include coronary artery vasospasm, endothelial damage, prothrombic effects and proapoptotic effects.
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Pretreatment prophylaxis with diltiazem allowed for 5-FU chemotherapy treatment by mitigating cardiovascular side effects.
Ethics statements
Patient consent for publication
Footnotes
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Contributors KB was the primary author of the case background, presentation, discussion and conclusion. AG was the author of the abstract and participated in clinical management. MK participated in clinical management. AR participated in manuscript concept and outline editing.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.
References
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