Assessment of cardiotoxicity in Immunity Checkpoint Blockers and other cancer therapies

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Background: Lung cancer is a leading cause of death from cancer death worldwide, and non-small-cell lung cancer (NSCLC) accounts for 85% of all lung cancer cases. Advances in NSCLC treatment using tyrosine kinase inhibitors (TKI) and immunity checkpoint blockers (ICB) have led to improved survival. However, there is a growing concern that cardiotoxicity associated with novel cancer therapies may lead to premature morbidity among survivors. Unfortunately, heart damage due to cardiotoxicity is often not recognized until manifested through acute or chronic cardiovascular events. Significance/Impact: Given their proven clinical efficacy in improving cancer outcomes and potential for expanded use in VA patients, there is an urgent need to better understand the risk and impacts of cardiovascular toxicity associated with use of TKI and ICB in clinical practice. The information gained from this pilot study will enable the conduct of large-scale population-based studies to identify clinical manifestations of cardiotoxicity, quantify the incidence of related cardiovascular disease over time, identify risk factors for cardiotoxicity associated with specific treatments, duration, and dose, and explore biomarkers that may serve as early warning signals of potential heart damage. Results may also facilitate research into cardiotoxicity associated with other cancer therapies and other types of cancer. Innovation: A significant challenge to population-based studies of cancer-related cardiotoxicity is the lack of validated algorithms to identify cardiotoxicity in observational data sources that reflect real-world clinical practice across multiple institutions. Therefore, developing and validating algorithms for quantifying and monitoring cardiovascular events in patients receiving alternative therapies would facilitate population-based research on the long-term effects of cancer treatments among survivors, and assist in long-term surveillance of novel cancer therapies to supplement clinical trial data. Benefits of conducting this research in the VA include the large number of veterans who receive care through the VA, the availability of clinical detail for all VHA patients nationwide through the VA Informatics and Computing Infrastructure (VINCI), and the availability of an NLP algorithm previously validated to extract echocardiogram results from clinical notes in VA medical records. We will focus our pilot analysis on patients with NSCLC due to the limited prior research on cardiotoxicity in patients with NSCLC. Specific Aims: This pilot study will develop and validate operational definitions of cardiovascular events representing potential clinical manifestations of cardiotoxicity to facilitate future investigations into cardiotoxicity associated with ICB and TKI using a population-based framework. Specific Aims are: 1) Develop and validate a structured algorithm for identifying cardiovascular events in patients who initiate NSCLC cancer therapy with ICI, TKI, or chemotherapy; and 2) Quantify the incidence of cardiovascular events, overall and by time frame (early versus late effects), and specific cardiac conditions. Methods: The study will use data for patients undergoing treatment for NSCLC in the VA during 2014-2019 and will incorporate three data sources: 1) administrative data on patient encounters, diagnoses, procedures, and medications; 2) data routinely available in EMR such as laboratory tests and vital signs; and 3) echocardiogram test results stored in unstructured clinical notes that will be queried using a natural language processing (NLP) algorithm. Definitions of cardiovascular events will be validated in sampled and abstracted medical records, and used to develop pilot data on cardiotoxicity incidence and type for a subsequent IIR. Implementation/Next Steps: Ultimately, this pilot study will develop and validate indicators of cardiotoxicity in patients undergoing NSCLC therapy that can be used across multiple clinical practices to facilitate future investigations into trends, prevention, and outcomes of patients with cancer who are at risk of cardiotoxicity.