Evaluation of Cardiotoxic Effects of Non-Small Cell Lung Cancer (NSCLC) Treatments: Insights from Multiple Databases in the United Kingdom

Abstract

Cancer and heart diseases are two of the major causes of death in the world. In the last few decades, there is a rapid development in cancer therapies and early detection strategies, hence the death rates caused by cancer have decreased. Although survival rates have improved, it is observed that cardiovascular disease has become the second leading cause of long-term morbidity and fatality among cancer survivors. Thus, the risk of cardiotoxicity is one of the major limitations of oncology drug development. Cardiotoxicity can occur during any stage of the cancer, and it includes, but is not limited to, subclinical myocardial toxicity, ischemia, hypertension, supraventricular and ventricular arrhythmias, systolic and diastolic cardiac dysfunction, coronary artery disease and heart failure. Therefore, the aim of this study was to investigate the association between non-small cell lung cancer (NSCLC) drugs and cardiotoxicity by using real-world data and clinical trials data available from public domains, reports and published literatures. A systematic review using several electronic databases was completed to evaluate randomised controlled trials data, in which cardiotoxicity was developed in non-small cell lung cancer patients after the administration of anticancer drugs. A full version protocol of this systematic review (CRD42020191760) is published on PROSPERO. A total of 1785 records were identified using specific search terms through the databases and registers; 74 eligible studies were included for data extraction. Based on data extracted from the included studies, anticancer drugs for NSCLC that reported to be associated with cardiovascular events included bevacizumab, carboplatin, cisplatin, crizotinib, docetaxel, erlotinib, gemcitabine and paclitaxel. Hypertension was the most reported cardiotoxicity as 30 studies documented this cardiovascular adverse event. Other reported treatment-related cardiotoxicities included arrhythmias, atrial fibrillation, bradycardia, cardiac arrest, cardiac failure, coronary artery disease, heart failure, ischemia, left ventricular dysfunction, myocardial infarction, palpitations, and tachycardia. A feasibility assessment was conducted to identify the most suitable database for investigating the association between non-small cell lung cancer and cardiotoxicity. A total of 103 data sources were identified from the Health Data Research Innovation Gateway and public domain using the search term ‘cancer’. Data sources which healthcare settings are primary care only were not suitable for this research question. Primary care only data is a major limitation for oncology studies as oncology treatment and follow-ups are mostly followed in secondary care settings. Consequently, only 2 eligible data sources (#34 and #54) were included for data extraction. An observational study based on a retrospective design using real-world data from the DEFINE database in England was performed. Monthly secondary data of 40 shortlisted drugs (20 anticancer drugs and 20 cardiology drugs) from April 2017 to July 2022 were extracted. From the correlation matrix, it can be concluded that hypertension was the most associated cardiovascular disease with the 20 shortlisted oncology drugs. A pharmacovigilance study was conducted utilising the UK Yellow Card System. All NSCLC drugs available within the UK Yellow Card System were shortlisted. Proportional reporting ratio (PRR) and reporting odds ratio (ROR) were calculated to detect signals. The total number of adverse events reported was 128,214 with 6133 reports being cardiovascular adverse reactions. Alectinib had the highest signal for potential cardiovascular adverse events among the drugs analysed, as indicated by both the highest ROR and PRR values. Due to drug-induced cardiotoxic complications, it is important to understand the suspected associations in order to maintain a benefit-risk balance between therapeutic gain and risk of cardiotoxicity. The combined findings of the systematic review, the pharmacoepidemiology study and the pharmacovigilance report have elucidated the types of cardiotoxicities associated with certain NSCLC therapeutics. To enhance the therapeutic management of NSCLC, continued research on identifying patients at elevated risk of cardiovascular adverse events as well as implementation of early detection and screening strategies are imperative.