ILAs in CT Lung Cancer Screening Population

Study Overview
=================
Brief Summary
-----------------
Interstitial Lung Abnormalities (ILA) have been previously defined as nondependent changes affecting more than 5% of any lung zone on computed tomography (CT) scans of the lung. Several studies suggest that the prevalence of ILA in participants in non-pulmonary research studies ranges anywhere from 7-9%. Work over the last decade has shown that, despite previous characterization as an asymptomatic research finding, ILA has significant clinical and biological consequences. These include reduced exercise capacity, functional limitations, decreased lung volumes, increased mortality, and in some cases histopathology similar to Idiopathic Pulmonary Fibrosis (IPF). ILA have been detected in lung cancer screening cohorts, where the prevalence of ILA is estimated to be between (10%-20%) to those noted in other research cohorts. Given that a significant proportion of those will have progression, CT lung cancer screening (CTLS) cohorts represent an ideal catchment population for future research and clinical trials. Lahey Hospital and Medical Center was one of the earliest clinical centers to develop a CTLS program in the country. Investigators propose to qualitatively characterize ILA in a large clinical CTLS population.

Detailed Description
-----------------
Investigators propose a retrospective, single-center study with following aims: Characterize the prevalence and incidence of ILA at baseline and 5 year follow-up, respectively, and associated imaging phenotypes in CTLS cohort. Baseline qualitative ILA features associated with clinical outcomes: Lung Cancer, Hospitalization, and Mortality. Baseline qualitative ILA features associated with progressive ILA and fibrotic lung disease. Clinical opportunity: to determine the % of CTLS patients with ILA who are at risk for progressive and development of fibrotic lung disease and who would benefit from specialized care referral and potential enrollment in clinical trials utilizing proven antifibrotic therapies Patient Selection: All clinical CT Lung Cancer Screening (CTLS) patients at Lahey Hospital and Medical Center (LHMC), Burlington, MA from January 1st, 2012 through September 30th, 2014 who had an in network primary care physician (n=1703). Patients with T4 screening scans will be scored for progression (n=653). To qualify for our study, patients had to satisfy the National Comprehensive Cancer Network (NCCN) Guidelines® Lung Cancer Screening Version 1.2012 high-risk criteria for lung cancer. Based on the NCCN Guidelines®, individuals eligible for lung cancer screening can be classified into NCCN group 1 and 2 as previously described. Patients in both groups were asymptomatic and had a physician order for CTLS, were free of lung cancer for ≥ 5 years, and had no known metastatic disease. Clinical Variables: Clinical variables were collected prospectively as part of the CTLS program and stored in a centralized data repository. Additional clinical variables not already available in this data repository will be collected retrospectively by manual review of the electronic medical record or pulled directly from the EMR and stored utilizing a custom-designed database (FileMaker ProVersion 11; Filemaker Inc, Santa Clara, California). Data was obtained through September 30th, 2019, patient demographics, past medical history, PFTs, immunization records, whether the patient was managed by a pulmonologist, and for hospital admissions with principal admission diagnoses. Hospital admissions will be collected using Lahey administrative coding data. Principal admission diagnoses of COPD, PNA, and CHF will be characterized based on diagnosis codes per 2018 Center for Medicare and Medicaid Services (CMS) condition-specific measures. CT Imaging: Clinically acquired, CTLS examinations which were performed on ≥64-row multidetector CT scanners (LightSpeed VCT and Discovery VCT [GE Medical Systems, Milwaukee, Wisconsin]; Somatom Definition [Siemens AG, Erlangen, Germany]; iCT [Philips Medical Systems, Andover, Massachusetts]) at 100 kV and 30 to 100 mA, depending on the scanner and the availability of iterative reconstruction software. Axial images were obtained at 1.25- to 1.5-mm thickness with 50% overlap and reconstructed with both soft tissue and lung kernels. Qualitative ILA Scoring: CT images will be scored utilizing Philips Intellispace PACS version 4.4 with clinical grade monitors. Scoring will be performed independently by two thoracic radiologists as described previously. Scores that are discordant between the two radiologists will be scored by a third by a pulmonologist with expertise in ILD. ILA: The presence of ILA features will be scores as (Yes/No/Indeterminate). Indeterminate will be defined as features identified unilaterally/focal involvement. ILA features that will be scored include: A) non dependent ground glass, B) reticular abnormalities, C) traction bronchiectasis and D) honeycombing. A) Non Dependent ground glass: (Yes/No/Indeterminate) defined as hazy increased attenuation of the lung with preservation of bronchial and vascular margins. B) Reticular abnormalities: (Yes/No/Indeterminate) defined as a collection of innumerable small linear opacities that, by summation, produce an appearance resembling a net. C) Traction Bronchiectasis: (Yes/No/Indeterminate) defined Traction bronchiectasis and traction bronchiolectasis respectively represents irregular bronchial and bronchiolar dilatation caused by surrounding retractile pulmonary fibrosis. D) Honeycombing: (Yes/No/Indeterminate) defined on CT as clustered cystic air spaces, typically of comparable diameters on the ordered of 3-10 mm but occasionally as large as 2.5 cm. Pattern: The overall pattern/Type of ILA findings will also be scored as the following: Subpleural, centrilobular, mixed or consistent with ILD (see UIP below). Subpleural: Defined as less than 1 cm from the pleural surface. Centrilobular: Defined as region of the bronchiolovascular core of the secondary pulmonary lobule. Location: Overall location ILA will then be scored as Upper lobe, lower lobe or diffuse. Extent: Overall extent of disease will be scored as Mild, Moderate and Marked. Usual Interstitial Pneumonia: Finally, the subset of scans that have evidence of fibrotic disease defined as traction bronchiectasis/honeycombing will then be classified as consistent with usual interstitial pneumonia (UIP) (Yes/Probable/No) based on Fleischner Criteria. UIP defined as Honey-combing with basal and subpleural distribution. Progression: The subset of patients who have had their T4 (5 year post baseline) screening scanned will be independently scored as above and in addition will be compared to their baseline scans and scored for progression: Stable, improved, and progressed.

Official Title
-----------------
Interstitial Lung Abnormalities--Qualitative Imaging Cohort Study in CT Lung Cancer Screening Population

Conditions
-----------------
Interstitial Lung Disease, IPF

Intervention / Treatment
-----------------
* Other: Retrospective observational study


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patient who have undergone low-dose screening CT scan for lung cancer as part of the LHMC CTLS program from January 1, 2012 through September 30, 2014, with an in-network PCP. Exclusion Criteria: Any patient that does not meet inclusion criteria.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| CT Lung Cancer Screening Patients<br>All CT Lung Cancer Screening patients at LHMC from January 1st, 2012 to September 30th, 2014 with an in-network PCP that had baseline CT scans will be scored. A subset of these patients with T4 screening scans will be scored for progression. | Other: Retrospective observational study<br>* No intervention to occur<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevalence of ILA at baseline | Both presence and absence of ILA, as well as phenotypes, will be described for the entire cohort. | 6 months | 
| Association between baseline ILA (presence/absence) and time to mortality, time to first hospitalization, and time to development of cancer in the full cohort | Kaplan-Meier plots will be generated to visualize the associations between ILA variables and cancer, hospital admission and mortality. The log-rank test will be used to evaluate for a significant association. Cox regression proportional hazards models will be used to test for this association in both univariate and multivariable models. The multivariable model will be adjusted for age, sex, smoking status and pack years exposure. | 6 months | 
| Progression of ILA | Progression of ILA, defined as worsening of existing ILA or incidence of ILA over 5 years, will be described for the subset of patients with T4 imaging at 5 years. Univariate and multivariable analyses using logistic regression will be performed to test for associations between qualitative ILA characteristics (presence and absence, as well as individual phenotypes in separate models) and progression (yes/no). Stable and improved will be considered no progression, while incident ILA and worsening of existing ILA will be considered progression. Models will be checked for influential points. Multivariable models will be adjusted for sex, age, currently smoking, and pack years exposure. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Association between phenotypes of ILA and outcomes | Using Kaplan-Meier plots and Cox regression analysis to examine association between phenotypes of ILA with time to first hospitalization, cancer, and mortality. The proportional hazards assumption will be checked for all Cox regression models. | 6 months | 
| Association between ILA and time to cause-specific mortality, hospitalization. | Investigators will investigate the association between ILA (presence/absence) and time to cause-specific mortality (pulmonary, cardiac, cancer, other), as well as cause-specific hospitalization based on primary diagnosis (COPD, PNA, and CHF). The proportional hazards assumption will be checked for all Cox regression models. | 6 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Interstitial Lung Disease, Interstitial Lung Abnormalities