Cardiotoxicity in Locally Advanced Lung Cancer Patients Treated With Chemoradiation Therapy

Study Overview
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Brief Summary
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This observational cohort will evaluate the cardiovascular effects of chemoradiation used to treat locally advanced, non-small cell lung cancer. Patients will be enrolled prior to the start of therapy and followed during and for at least 2 years after therapy with echocardiograms, nuclear stress tests, blood sampling, and quality of life surveys.

Detailed Description
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Lung cancer is both the most common malignancy worldwide and the leading cause of cancer death in the US. While radiation therapy is highly effective for many solid tumors, thoracic radiation therapy carries a risk of cardiovascular morbidity and mortality that limits critical gains in cancer control and survival. The investigators will perform detailed cardiovascular phenotyping using biologic and imaging markers to define functional and physiologic perturbations that occur with radiation therapy. The study will provide insights into how cardiovascular risk factors and disease impact these biologic and functional changes. The investigators will also determine which radiotherapy dose-volume metrics are indicative of subclinical cardiotoxicity.

Official Title
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Cardiotoxicity in Locally Advanced Lung Cancer Patients Treated With Chemoradiation Therapy: A Prospective Longitudinal Cohort

Conditions
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Cardiotoxicity, Lung Cancer Stage III, Lung Cancer Stage II, Radiation Toxicity

Intervention / Treatment
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* Other: Chemoradiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: At least 18 years of age Histologically confirmed or clinically diagnosed non-small cell lung cancer where the plan is for definitive treatment that includes radiation Able to give written informed consent Exclusion Criteria: Pregnant or breast-feeding Prior treatment with anthracyclines Radiation treatment not expected to involve any heart exposure as determined by treating provider ECOG performance status greater than 2 Vulnerable patients, including pregnant women and prisoners Contraindication to rest/vasodilator stress PET/CT, including: asthma with ongoing wheezing at time of enrollment; known Mobitz Type II AV block, 3rd degree AV block, or sick sinus syndrom, without a pacemaker; systolic blood pressure less than 90mmHg; known hypersensitivity to Regadenoson and adenosine; profound sinus bradycardia (heart rate less than 40bpm).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Cohort<br>Patients with locally advanced non-small cell lung cancer | Other: Chemoradiation<br>* Patients will be treated with definitive concurrent chemoradiation with curative intent as determined by their medical and radiation oncologists. We will consider timing of initiation and discontinuation, type, and cumulative dose of platinum based chemotherapy. We will also consider dose, duration, and type of immunotherapy. Radiation therapy will be delivered via proton or proton therapy. Our primary radiation therapy dose-volume exposures are whole heart volumetric dose. As secondary exposures, we will comprehensively define radiation therapy dose parameters to the right ventricle, entire left ventricle, left ventricle segments, coronary arteries, and mean heart dose.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| High Sensitivity C-Reactive Protein | Change in hsCRP from baseline | up to 12 months | 
| Growth Differentiation Factor 15 | Change in GDF-15 from baseline | up to 12 months | 
| Placental Growth Factor | Change in PIGF from baseline | up to 12 months | 
| Left Ventricular Strain | Change in echo-derived measures of LV peak systolic strain (longitudinal) from baseline | up to 12 months | 
| Ventricular Arterial Coupling | Change in echo-derived measures of ventricular-arterial coupling (Ea/Ees) from baseline | up to 12 months | 
| Coronary Flow Reserve (CFR_ | Change in PET/CT derived CFR from baseline | 6 months | 
| Overall Survival (2 Year) | All-cause mortality assessed by electronic medical record (EMR) review | 24 months | 
| Cardiovascular Specific Mortality (2 Year) | Cardiovascular specific mortality assessed by EMR review | 24 Months | 
| Major Cardiovascular Events (2 Year) | Incidence of MCE assessed by EMR review and patient interview | up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| High-Sensitivity Troponin T | Change in hsTnT from baseline | up to 12 months | 
| N-type pro Brain Natriuretic Peptide | Change in NTproBNP from baseline | up to 12 months | 
| Left Ventricular Ejection Fraction (2D) | Change in echo-derived LVEF from baseline | up to 12 months | 
| Right Ventricular Fractional Area Change (RAC) | Change in echo-derived RAC from baseline | up to 12 months | 
| Right Ventricular Longitudinal Strain | Change in echo-derived RV longitudinal strain from baseline | up to 12 months | 
| Circumferential Strain | Change in echo-derived circumferential strain from baseline | up to 12 months | 
| Diastolic Function | Change in echo-derived measures of diastolic function from baseline | up to 12 months | 
| Valvular Disease | Change in echo-derived measures of valvular disease (degree of regurgitation or stenosis) from baseline | up to 12 months | 
| Left Ventricular Ejection Fraction (3D) | Change in 3D echocardiography derived LVEF from baseline | up to 12 months | 
| Left Ventricular systolic strain (3D) | Change in 3D echocardiography derived measures of LV systolic strain from baseline | up to 12 months | 
| Left Ventricular Twist and Torsion | Change in 3D echocardiography derived measures of LV twist and torsion from baseline | up to 12 months | 
| Global and Regional Myocardial Blood Flow at Rest | Change in PET/CT derived measures of global and regional myocardial blood flow at rest from baseline | up to 6 months | 
| Global and Regional Myocardial Blood Flow at Stress | Change in PET/CT derived measures of global and regional myocardial blood flow at stress from baseline | up to 6 months | 
| FACIT Fatigue Score | Change in FACIT Fatigue score from baseline. Score ranges from 0-52. Higher scores indicated less fatigue. | up to 5 years | 
| FACIT Dyspnea Score | Change in FACIT Dyspnea score from baseline. Score ranges from 0-30. Higher scores indicate more dyspnea. | up to 5 years | 
| Godin Leisure Time Exercise Score | Change in Godin Leisure Time Exercise Score from baseline. Higher scores indicate higher levels of physical activity. | up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Radiation Therapy Cardiotoxicity, Cardiovascular Risk Factors, Lung Cancer, Cardiovascular Phenotyping, Radiation Therapy, Cardiovascular Disease, Cardio-Oncology