Treatment-Related Coronary Disorders of Fluoropyrimidine Administration: A Systematic Review and Meta-Analysis

Abstract

Background: Coronary disorders are recognized as the most common manifestation of fluoropyrimidine-related cardiotoxicity in clinical practice. However, there are limited and conflicting data on the incidence and profiles of fluoropyrimidine-related coronary disorders. In this meta-analysis, we aimed to systematically assess the incidence of all-grade and grade 3 or higher fluoropyrimidine-related coronary disorders, and further explore the factors that influence its occurrence.Methods: Studies reporting the fluoropyrimidine-related coronary disorders were retrieved from a systematic search of English literature in the PubMed, Web of Science, Medline, and Cochrane database from 1 Jan 2001, to 1 Jan 2022. The NIH assessment tool was used to evaluate the quality of each study. The data of basic study characteristics, treatment details, and results of coronary toxicities were extracted. According to the results of the heterogeneity test (I2 and p-value statistic), a random-effect model or fixed-effect model was selected for the pooled analysis of the incidence of adverse coronary events. Subgroup analysis was conducted to further explore the risks influencing the occurrence of fluoropyrimidine-related coronary disorders. The stability and publication bias of our results were evaluated by sensitivity analysis and Egger test, respectively.Results: A total of 63 studies were finally included in our pooled analysis, involving 25,577 patients. The pooled cumulative incidence of all-grade and grade 3 or higher coronary disorders was 2.75% (95% CI 1.89%–3.76%) and 1.00% (95% CI 0.62%–1.47%), respectively. The coronary disorders were most reported as myocardial ischemia (1.28%, 95% CI 0.42%–2.49%) and angina/chest pain (1.1%, 95% CI 0.54%–1.81%). Subgroup analysis revealed that studies in the female-only population seemed to have a lower incidence of fluoropyrimidine-related coronary disorders. The occurrence of adverse coronary events varied among different tumor types. Patients with esophageal cancer have the highest coronary toxicity (6.32%), while those with breast cancer have a relatively lower incidence (0.5%). Coronary disorders induced by 5-FU monotherapy are more frequent than that induced by capecitabine (3.31% vs. 1.21%, p < 0.01). Fluoropyrimidine combination therapy, whether combined with other chemotherapy drugs, targeted therapy drugs, or radiotherapy, significantly increased the incidence of coronary complications (p < 0.01).Conclusion: This meta-analysis has defined the incidence of fluoropyrimidine-related coronary disorders and depicted its epidemiological profiles for the first time, which may provide a reference for clinical practice in cancer management.

Fluoropyrimidine-induced hand-foot syndrome and cardiotoxicity: recommendations for the use of the oral fluoropyrimidine S-1 in metastatic colorectal cancer

“…Less frequently, cardiac arrhythmias, myocardial infarction, and even sudden death have been reported. 3 , 33 , 36 The risk of myocardial infarction during FP treatment is two times as high compared with what is expected (0.7% in FP compared with 0.3% in a matched cohort). 37 …”

“… 35 The overall reported mortality rate for 5-FU- or capecitabine-associated CVT in prospective studies varies between 0% and 2.2%. 36 …”

“…Indeed, cardiac complications have been reported less frequently for tegafur with uracil than for 5-FU or capecitabine, and murine studies adding uracil to tegafur clearly reduced CVT as compared with tegafur alone. 33 , 36 , 51 In a recent review, no serious cardiovascular events were reported in published phase II or III studies with S-1. 52 …”

Development and validation of a nomogram to predict cardiac death after radiotherapy for esophageal cancer

“…The most commonly used chemotherapeutic drugs for EC include cisplatin (DDP), 5‐fluorouracil (5‐FU), and doxorubicin (Dox) [ 4 ]. Cisplatin produces cardiotoxicity through DNA damage, ROS‐mediated oxidative stress, inflammation, and MAPK signaling pathway activation [ 5 ]; 5‐FU leads to activation of protein kinase C, increased nitric oxide, imbalance of oxygen supply and demand, and cardiac arterial thrombosis, and the direct cardiotoxic effects lead to coronary toxicity, arrhythmia, blood pressure changes and even cardiogenic shock [ 6 , 7 , 8 ]; Dox causes cumulative and dose‐dependent cardiotoxicity through oxidative stress and apoptosis [ 9 ]. Immunotherapy is a major advance in cancer theatment, although the reported incidence of immune‐related cardiovascular events is 1.14%–5% (including myocarditis 0.3%–1.4%, arrhythmia 3.6%–4.8%, pericardial disease 1.74%, vasculitis 0.27%, acute coronary syndrome (ACS) 0.95%–7.0% and heart failure (HF) 1.6%), the mortality rate can be as high as 50%, and the possible etiology of cardiovascular immune‐related adverse events (IRAE) includes local T cell activation, cross‐reactivity of antitumor T cells with myocardial antigens, or systemic immune activation [ 10 ].…”