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
