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Immune Checkpoint Inhibitors

Calcium

Calcium, Dietary

* Electrocardiogram (ECG).
* Echocardiogram: A comprehensive evaluation of systolic and diastolic function, ventricular and atrial geometry will be performed. Special attention will be given to acquire a 3D measurement of left ventricular ejection fraction (LVEF) and to perform deformation imaging of left ventricle (global longitudinal strain (GLS)). The right ventricular function will be evaluated by tricuspid annular plane systolic excursion (TAPSE) and peak systolic velocity S' derived from color coded tissue Doppler imaging (TDI). Diastolic dysfunction will be based on average E/e' ratio \> 15 and left atrial (LA) area \> 30 cm2.

Cardiology consultation

Calcium score. This will be performed at baseline, 12 and 24 months. The scans at 12 and 24 months will be combined, if possible, with standard of care scans for cancer treatment.

Chest Computed Tomography (CT) without contrast

* FMD
* PAT

This aspect of the study will only be performed in the patients included by the Antwerp University Hospital due to organizational/practical issues.

Non-invasive endothelial function tests

An ECG will be taken prior to each ICI cycle during the first three months of treatment.

Electrocardiogram

An extra serum sample will be taken at baseline, 3, 6, 12, 24 months and in case of sudden cardiac problems. This will subsequently be analysed to determine high-sensitivity troponin I, high-sensitivity troponin T and NT-proBNP.

Extra serum sample (7.5 mL)

Christof Vulsteke, Prof

Danielle Delombaerde, PharmD

Hans Prenen, Prof

Sanne Wouters

Constantijn Franssen, Dr

The goal of this prospective, multicentre study is to investigate short- and long-term cardiovascular effects in cancer patients treated with immune checkpoint inhibitors (ICIs).

The main question\[s\] it aims to answer are:

* To investigate troponin and NT-proBNP values in patients receiving ICIs and their association with ICI-induced CV abnormalities and MACEs.
* Study the calcium score, systolic, and diastolic (dys)function.
* Evaluate associations between patient/disease characteristics / transthoracic echocardiography parameters / electrocardiography parameters and troponin / NT-proBNP levels.

Participants will be closely monitored by performing the following additional visits and testing:

* Chest CT scan prior to treatment start, after 12 and 24 months.
* Consultation with a cardiologist at baseline, 3, 6, 12 and 24 months, who will perform an electrocardiogram and echocardiogram.
* One additional blood sample prior to treatment start, after 3, 6, 12 and 24 months. An extra blood sample could be taken in case of sudden heart problems.
* Non-invasive endothelial function tests prior to treatment start, after 12 and 24 months.

The increasing use of immune checkpoint inhibitors (ICIs) in the treatment of both advanced and early stages of various malignancies has resulted in a substantial increase in the incidence of cardiovascular immune related adverse events (irAEs). The current guidelines are based on anecdotal evidence and expert opinions due to the lack of solid data and prospective studies. Therefore, cardiac monitoring, in patients receiving ICIs, is often not implemented by oncologists as many questions remain unanswered. Hence, the urgent need to investigate the possible short and long term cardiovascular effects of ICIs.

The investigators developed a multicentre, prospective study in which patients with a solid tumour eligible for ICI treatment will be enrolled. The study exists of routine investigations of blood parameters (troponin and (N-terminal) brain-type natriuretic peptide levels in particular) and a thorough cardiovascular follow-up on fixed time points during a period of two years. The cardiovascular follow-up consists of continuous remote patient monitoring, routine cardiology consultations including electrocardiograms, transthoracic echocardiograms, CT-scans for calcium scoring and non-invasive endothelial function tests. Associations between these blood parameters and short and long term cardiovascular irAEs will be statistically analysed.

This project will allow for a better estimate of the incidence of both short and long-term cardiovascular irAEs in a 'real world' patient population receiving ICIs. If the investigators are able to accurately predict and detect short- and long-term cardiovascular irAEs in an early (and subclinical) stage by correct implementation and interpretation of existing cardiac markers, they could be managed early on in a more effective manner.

Extensive CArdioVAscular Characterization and Follow-up of Patients Receiving Immune Checkpoint Inhibitors

Extensive CArdioVAscular Characterization and Follow-up of Patients Receiving Immune Checkpoint Inhibitors: a Prospective Multicentre Study

For the primary endpoint, the cumulative incidence of troponin elevation will be calculated with death as a competing risk. Cumulative incidences and corresponding 95% confidence intervals will be reported and a cumulative incidence plot will be used to visualize the results.

Cumulative incidences and 95% confidence intervals, considering death as a competing event.

Linear mixed effects model with a random intercept per subject to account for the correlation measurements coming from the same individual.

Joint model combining a linear mixed model for troponin and a sub-distributional proportional hazards model for the time-to-event taking into account death as a competing event for CV abnormality and MACE.

Cumulative incidences and 95% confidence intervals

Linear mixed effects model with a random intercept per subject to account for the correlation measurements coming from the same individual. This model will be extended with patient and treatment characteristics and their interaction with time, to evaluate their impact on the evolution of these parameters.

Bland-Altman curves and intraclass correlation coefficient (ICC) based on a two-way mixed effects model. The ICC and 95% confidence interval will be reported.

Flow mediated dilatation: dilatation % from baseline to maximal post-occlusion diameter.

Peripheral arterial tonometry ratio: based on the response to reactive hyperemia using post and pre-occlusion values

Spots Global Cancer Trial Database for cardiac abnormalities, variable