Fluoropyrimidine-Induced Cardiotoxicity: Manifestations, Mechanisms, and Management

Layoun, Michael; Wickramasinghe, Chanaka D.; Peralta, Maria V.; Yang, Eric H.

doi:10.1007/s11912-016-0521-1

Cited by 72 publications

(71 citation statements)

References 71 publications

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“…Familiarity with the literature highlighting the reversibility of trastuzumab-associated cardiotoxicity; use of biomarkers to predict cardiotoxicity in patients receiving cancer therapy; and increased comfort among cardiologists in managing cardiotoxicity, likely account for these changing results in our survey [28][29][30]. The second case described the most common manifestation of 5-FU cardiotoxicity: angina [31][32][33]. More oncologists decided to switch therapy to raltitrexed rather than rechallenge with 5-FU.…”

Section: Discussionmentioning

confidence: 90%

An international survey of healthcare providers’ knowledge of cardiac complications of cancer treatments

et al. 2019

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Background: Cardio-oncology is a young sub-specialty that addresses the needs of cancer patients at risk of, or who have experienced cancer therapy related cardiac dysfunction (CTRCD). This study assessed clinicians' understanding of cardio-oncology, opinions towards current practice, and approach to diagnosing and managing CTRCD. Methods: A 45-question survey was administered online via Survey Monkey and WeChat to health care providers (HCPs) comprising of cardiologists, oncologists, and others from September 2017 to March 2018. Implementation of the survey followed a modified Dillman's Total Design Method. Results: In total, 160 responses were collected from 22 countries; majority were from cardiologists (53.8%) and oncologists (32.5%). The remaining 13.7% identified themselves as "others," including general internists, cardiooncologists, pediatric oncologists, radiation oncologists, cardiac rehabilitation therapists, nurse practitioners, research students, and pharmacists. In the setting of metastatic cancer, there was a difference in risk tolerance for cardiotoxicity between subspecialties. In this case, more cardiologists (36.7%) accepted a 5-10% risk of cardiotoxicity compared to oncologists (20.0%). Majority of cardiologists felt that cardiotoxicity should be monitored, even in asymptomatic cancer patients (55.8%). Only 12% of oncologists selected this response. In contrast, 50.0% of oncologists reported that cardiologists should be involved only when patients develop cardiotoxicity. In comparison, 6.5% of cardiologists selected this response. Majority of cardiologists stated that cardio-oncology clinics would significantly improve cancer patients' prognosis (88.3%); only 45.8% of oncologists shared this opinion. Of all respondents, 66.9% stated they were familiar with a variety of international guidelines for managing cardiotoxicity. Of all oncologists, 65.3% indicated that they referred to these guidelines for clinical decision making. Conclusions: Despite the growth of cardio-oncology clinics, there are significant knowledge gaps regarding prevention and treatment strategies for CTRCD among health care providers. Knowledge translation from guidelines and collaboration between cardiologists and oncologists are needed to improve cardiovascular outcomes of cancer patients.

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Section: Discussionmentioning

confidence: 90%

An international survey of healthcare providers’ knowledge of cardiac complications of cancer treatments

et al. 2019

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“…In most 5FU or capecitabine-related acute coronary syndromes for which coronary angiography was timely performed, no significant obstructive epicardial coronary artery disease was found, suggesting that microvascular dysfunction or 5-fluorouracil and GLP-1 in endothelial senescence BJP coronary artery spasm are the anatomical substrate of 5FU or capecitabine-associated myocardial ischaemia (Layoun et al, 2016). Coronary artery spasm has in fact been demonstrated in anecdotal cases (Goldsmith et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…Myocardial ischaemia is a potentially life-threatening and not uncommon complication of chemotherapy with 5FU or capecitabine (Polk et al, 2014;Layoun et al, 2016). In most 5FU or capecitabine-related acute coronary syndromes for which coronary angiography was timely performed, no significant obstructive epicardial coronary artery disease was found, suggesting that microvascular dysfunction or 5-fluorouracil and GLP-1 in endothelial senescence BJP coronary artery spasm are the anatomical substrate of 5FU or capecitabine-associated myocardial ischaemia (Layoun et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

5‐fluorouracil causes endothelial cell senescence: potential protective role of glucagon‐like peptide 1

Altieri

Murialdo

Barisione

et al. 2017

British J Pharmacology

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BACKGROUND AND PURPOSE5-fluorouracil (5FU) and its prodrug, capecitabine, can damage endothelial cells, whilst endothelial integrity is preserved by glucagon-like peptide 1 (GLP-1). Here, we studied the effect of 5FU on endothelial senescence and whether GLP-1 antagonizes it. EXPERIMENTAL APPROACHEA.hy926 cells were exposed to 5FU or sera from patients taking capecitabine, with or without pre-incubation with GLP-1. Senescence was identified by expression of senescence-associated β-galactosidase and p16INK4a and reduced cell proliferation. Soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1) and CD146 (marker of endothelial injury) were measured by ELISA before and at completion of capecitabine chemotherapy. RT-PCR, western blotting, functional experiments with signalling inhibitors and ERK1/2 silencing were performed to characterize 5FU-induced phenotype and elucidate the pathways underlying 5FU and GLP-1 activity. KEY RESULTSBoth 5FU and sera from capecitabine-treated patients stimulated endothelial cell senescence. 5FU-elicited senescence occurred via activation of p38 and JNK, and was associated with decreased eNOS and SIRT-1 levels. Furthermore, 5FU up-regulated VCAM1 and TYMP (encodes enzyme activating capecitabine and 5FU), and sVCAM-1 and CD146 concentrations were higher after than before capecitabine chemotherapy. A non-significant trend for higher ICAM1 levels was also observed. GLP-1 counteracted 5FU-initiated senescence and reduced eNOS and SIRT-1 expression, this protection being mediated by GLP-1 receptor, ERK1/2 and, possibly, PKA and PI3K. CONCLUSIONS AND IMPLICATIONS5FU causes endothelial cell senescence and dysfunction, which may contribute to its cardiovascular side effects. 5FU-triggered senescence was prevented by GLP-1, raising the possibility of using GLP-1 analogues and degradation inhibitors to treat 5FU and capecitabine vascular toxicity.

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“…Preexisting CAD and associated cardiovascular risk factors may increase the risk of cardiovascular events in those exposed to chemotherapy or radiation. This information dates back several decades with reports of a four-fold increase in cardiac events in patients with a cardiac history who received 5-fluorouracil, as well as significantly worsened left ventricular dysfunction in cardiac patients who receive anthracyclines [17,18]. In lymphoma patients previously treated with radiation, cardiac risk factors pose an increased threat compared to a non-cardiac population [19].…”

Section: Pre-treatment Risk Stratificationmentioning

confidence: 99%

Applications of Cardiac Computed Tomography in the Cardio-Oncology Population

Layoun

Yang

Herrmann

et al. 2019

Curr. Treat. Options in Oncol.

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Opinion statementThe increased risk for cardiovascular events in aging cancer survivors and those undergoing certain chemotherapeutic treatments has raised concern for more rigorous screening and surveillance methods above that of the general population. At this time, there are limited guidelines for how to best manage this vulnerable cohort. Questions regarding timing of screening, choice of imaging modality and risk reduction strategies-especially in those patients with known atherosclerotic disease-remain to be elucidated. Over a decade of case series, retrospective studies and clinical trials have shed light on the evolving role of cardiac computed tomography (CT) in this population, of which there is a relative paucity of data regarding its potential utility in the specific cardio-oncology population. Focusing on ability of cardiac CT to evaluate multiple cardiac and vascular structures, provide diagnostic and prognostic information, as well as assist interventional and surgical colleagues in surgical/percutaneous valve replacement and revascularization strategies is the premise for this review.

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Fluoropyrimidine-Induced Cardiotoxicity: Manifestations, Mechanisms, and Management

Cited by 72 publications

References 71 publications

An international survey of healthcare providers’ knowledge of cardiac complications of cancer treatments

An international survey of healthcare providers’ knowledge of cardiac complications of cancer treatments

5‐fluorouracil causes endothelial cell senescence: potential protective role of glucagon‐like peptide 1

Applications of Cardiac Computed Tomography in the Cardio-Oncology Population

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