Time for paying attention to fluoropyrimidine-associated cardiotoxicity: A pooled data analysis for epidemiology based on 60537 cases.

Abstract

12071 Background: With the rise of cardio-oncology discipline, treatment-related cardiotoxicity has become a growing concern. However, fluoropyrimidine induced cardiotoxicity has been underestimated for a long time. The aim of this study was to comprehensively investigate the incidence and profiles of the cardiotoxicity associated with fluoropyrimidine using a pooled data meta-analysis. Methods: A systematic literature review was performed using PubMed, Embase, Medline, Web of Science, Cochrane library databases and clinical trials on studies published between the establishment of each database and March 31, 2021, investigating fluoropyrimidine associated cardiotoxicity (FAC). The main outcome was pooled incidence of FAC, and the secondary outcome were specific treatment-related cardiac AEs. Random-effects or fixed-effects modeling was used for analyses according to the heterogeneity assessed by Cochran’s Q test. Subgroup analysis and meta-regression were conducted to explore the source of heterogeneity, and the incidence of FAC was compared among different clinical characteristics. The protocol was registered in PROSPERO (No. CRD42021282155). Results: Two hundred and six studies involving 60537 patients were included in this meta-analysis, covering 31 countries or regions in the world. The pooled incidence of FAC was 5.18% (95% CI 4.32%-6.10%) for all grade and 1.5% (95% CI 1.09%-1.96%) for grade 3 or higher. A total of 0.29% of patients died from severe cardiotoxicity. Cardiac ischemia and arrhythmia were the two most common cardiac AEs, occurring in 2.31% (95% CI 1.70%-3.00%) and 1.69% (95% CI 1.08%-2.42%) of patients, respectively. ECG alterations occurred in 5.85% (95% CI 3.4%-8.9%) of patients, indicating asymptomatic ECG alterations in a subset of the population. The incidence of cardiotoxicity varied among different regions, gender, cancer types and treatment regimens. Studies conducted in Asia outlined a significant higher pooled incidence of FAC than in Europe (χ2 = 4.47, p = 0.03) and America (χ2 = 4.49, p = 0.03). Female population had a lower pooled incidence than general population (χ2 = 9.90, p= 0.01). The highest pooled incidence was observed in esophagus cancer (10.53%, 95% CI 5.8%-16.35%), and the lowest occurred in breast cancer (3.66%, 95% CI 2.4%-5.12%). In addition, combination therapy, high cumulative dose, anthracycline addition, and pre-existing cardiac disorder significantly increased the risk of FAC ( p< 0.05). No obvious publication bias was detected by funnel plots and Egger’s test (p < 0.05), and the stability of our results was confirmed by the sensitivity analysis. Conclusions: FAC is not a rare condition during treatment containing fluoropyrimidines. Our results provide comprehensive global data on epidemiology of FAC, potentially representing an important reference on cancer management in clinical practice.