F-FDG-PET/CT Uptake by Noncancerous Lung as a Predictor of Interstitial Lung Disease Induced by Immune Checkpoint Inhibitors.

Rationale And Objectives: Immune checkpoint inhibitors (ICIs) have improved lung cancer prognosis; however, ICI-related interstitial lung disease (ILD) is fatal and difficult to predict. Herein, we hypothesized that pre-existing lung inflammation on radiological imaging can be a potential risk factor for ILD onset. Therefore, we investigated the association between high uptake in noncancerous lung (NCL) on F- FDG-PET/CT and ICI-ILD in lung cancer.

Methods: Patients with primary lung cancer who underwent FDG-PET/CT within three months prior to ICI therapy were retrospectively included. Artificial intelligence was utilized for extracting the NCL regions (background lung) from the lung contralateral to the primary tumor. FDG uptake by the NCL was assessed via the SUVmax (NCL-SUVmax), SUVmean (NCL-SUVmean), and total glycolytic activity (NCL-TGA)defined as NCL-SUVmean×NCL volume [mL]. NCL-SUVmean and NCL-TGA were calculated using the following four SUV thresholds: 0.5, 1.0, 1.5, and 2.0.

Results: Of the 165 patients, 28 (17.0%) developed ILD. Univariate analysis showed that high values of NCL-SUVmax, NCL-SUVmean (SUV threshold=2.0), and NCL-TGA (SUV threshold=1.0) were significantly associated with ILD onset (all p = 0.003). Multivariate analysis adjusted for age, tumor FDG uptake, and pre-existing interstitial lung abnormalities revealed that a high NCL-TGA (≥149.45) was independently associated with ILD onset (odds ratio, 6.588; p = 0.002). Two-year cumulative incidence of ILD was significantly higher in the high NCL-TGA group than in the low group (58.4% vs. 14.4%; p < 0.001).

Conclusion: High uptake of NCL on FDG-PET/CT is correlated with ICI-ILD development, which could serve as a risk stratification tool before ICI therapy in primary lung cancer.