Improving Pulmonary Function Following Radiation Therapy

Study Overview
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Brief Summary
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The purpose of this study is to develop radiation plans that will help preserve lung function in healthy tissue surrounding the tumor. We believe that 4DCT scans can be useful in designing radiation treatment plans that help us avoid healthy normal functioning lung tissue close to lung tumors. Currently 4DCT scans are used to help us determine exactly where the tumor is and how it moves when you breathe. In this study we will also use the 4DCT scans to try to identify high functioning normal lung tissue.

Official Title
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Improving Pulmonary Function Following Radiation Therapy

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Radiation: Standard fractionation
* Radiation: Stereotactic Body Radiation Therapy (SBRT)
* Procedure: Four Dimensional Computed Tomographic Imaging (4DCT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologic diagnosis of non-small cell lung cancer or lung metastasis from a solid tumor. One biopsy site is adequate for multiple sites of thoracic disease. Treatment includes localized radiation therapy with or without chemotherapy Karnofsky ≥ 60% Not pregnant per radiation oncology standard procedures Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Prior (within last 6 months) or future planned therapeutic surgery for the treatment of the existing lung cancer Prior thoracic radiotherapy Severe COPD defined as disease requiring an inpatient stay for respiratory deterioration within the past 3 months Oxygen dependence of > 2 L/min continuously throughout the day at baseline Known underlying collagen vascular disease or intrinsic lung disease that could complicate expected sequelae of radiation (idiopathic pulmonary fibrosis, Wegener's granulomatosis) Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

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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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard of Care<br>Subjects undergo four-dimensional computed tomographic imaging (4DCT) scans: 1 at simulation, and 2 scans at each of the 3 post-radiation therapy time points (3, 6, and 12 months). 4DCT determines lung tissue elasticity and for standard of care radiation treatment planning. Subjects undergo laboratory biomarker analysis, including spirometry, diffusion capacity (DLCO), and lung volumes (FEV, FEV1). Subjects complete a self-assessment, RTOG defined acute evaluation toxicity evaluation, RTOG late toxicity evaluation, and constitutional assessment. Radiation doses between 60-66 Gy using standard fractionation (1.8-2.0 Gy/fx) and 40-60 Gy stereotactic body radiation therapy (SBRT) hypofractionation schemes are utilized. Treatment volumes are at the discretion of the treating radiation oncologist and should follow standard of care. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Radiation: Standard fractionation<br>* 60-66y Gy delivered in 1.8-2.0 Gy fractions over 30-36 treatments<br>* Other names: Radiation;Radiation: Stereotactic Body Radiation Therapy (SBRT)<br>* 40-60 Gy delivered in 5-20 Gy fractions over 3-8 treatments<br>* Other names: Radiation;Procedure: Four Dimensional Computed Tomographic Imaging (4DCT)<br>* Subjects undergo a total of 7 research-ordered four dimensional computed tomographic imaging (4DCT) scans: 1 at simulation, and 2 scans at each of the 3 post-radiation therapy time points (3, 6, and 12 months). 4DCT determines lung tissue elasticity and for standard of care radiation treatment planning.<br>* Other names: 4DCT;|
| Experimental: Pulmonary Function Damage Reduction<br>All criteria and specifications in the standard of care arm are applicable for this arm, including the same 4DCT scans, and laboratory biomarker analysis. Subjects randomized to this arm of the trial will have the same prescribed radiation dose to the tumor volume and held to the same radiation dose criteria as the subjects in the standard of care arm (60-66 Gy using standard fractionation (1.8-2.0 Gy/fx) and 40-60 Gy stereotactic body radiation therapy (SBRT) hypofractionation). The fundamental difference will be radiation doses for these subjects will be redistributed away from regions predicted to cause the greatest reduction in pulmonary function if damaged. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Radiation: Standard fractionation<br>* 60-66y Gy delivered in 1.8-2.0 Gy fractions over 30-36 treatments<br>* Other names: Radiation;Radiation: Stereotactic Body Radiation Therapy (SBRT)<br>* 40-60 Gy delivered in 5-20 Gy fractions over 3-8 treatments<br>* Other names: Radiation;Procedure: Four Dimensional Computed Tomographic Imaging (4DCT)<br>* Subjects undergo a total of 7 research-ordered four dimensional computed tomographic imaging (4DCT) scans: 1 at simulation, and 2 scans at each of the 3 post-radiation therapy time points (3, 6, and 12 months). 4DCT determines lung tissue elasticity and for standard of care radiation treatment planning.<br>* Other names: 4DCT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pulmonary function, based on changes in tissue elasticity measured from 4DCT | The primary endpoint of this study will be the ratio of the tissue elasticity map following RT to the elasticity map before RT (i.e., the Jacobian ratio of (post RT /pre RT)) calculated from 4DCT at 3 months post-RT. Based on the randomness of our measurement technique, diminished expansion (i.e. substantial change) is defined as a Jacobian ratio <0.94 (i.e., less than 94% of the pre-RT value). | 3 months post RT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Temporal changes in reduced elasticity, Jacobian ratio | All statistical tests will be two-sided and assessed for significance at the 5% level. | During therapy to 12 months post-RT | 
| Temporal changes in increased elasticity determined by the volume of lung where expansion is improved | All statistical tests will be two-sided and assessed for significance at the 5% level. | During therapy to 12 months post-RT | 
| Temporal changes in fraction of expanding lung determined by the volume of lung where meaningful expansion occurs | All statistical tests will be two-sided and assessed for significance at the 5% level. | During therapy to 12 months post-RT | 
| Validation in consistency of tissue elasticity changes measured with values predicted based on existing radiation dose response curves | All statistical tests will be two-sided and assessed for significance at the 5% level. | Up to 12 months post-RT | 
| Changes in PFTs | All statistical tests will be two-sided and assessed for significance at the 5% level. | Pre-RT up to 12 months post-RT | 
| Change in level of plasma TGF-beta1 measured by molecular specific enzyme linked immune sandwich assay | All statistical tests will be two-sided and assessed for significance at the 5% level. | Baseline up to 12 months post-RT | 
| Change in level of plasma cytokines measured by LINCOplex (microsphere-based sandwich immunoassay) | All statistical tests will be two-sided and assessed for significance at the 5% level. | Baseline up to 12 months post-RT | 
| Variation of the tissue elasticity calculated between scan 1 and scan 2 at each time point will be quantified and compared to longitudinal changes in tissue elasticity | All statistical tests will be two-sided and assessed for significance at the 5% level. | Up to 12 months post-RT |