Radiation and immune checkpoint inhibitor-mediated pneumonitis risk stratification in patients with locally advanced non-small cell lung cancer: role of functional lung radiomics?
Authors: Thomas Hannah Mary T , Hippe Daniel S , Forouzannezhad Parisa , Sasidharan Balu Krishna , Kinahan Paul E , Miyaoka Robert S , Vesselle Hubert J , Rengan Ramesh , Zeng Jing , Bowen Stephen R 
Published: May 2022

Abstract
Background: Patients undergoing chemoradiation and immune checkpoint inhibitor (ICI) therapy for locally advanced non-small cell lung cancer (LA-NSCLC) experience pulmonary toxicity at higher rates than historical reports. We investigated the role of novel functional lung radiomics, relative to functional lung dosimetry and clinical characteristics, for pneumonitis risk stratification in LA-NSCLC.Methods: Thirty-nine patients with LA-NSCLC were prospectively enrolled on the FLARE-RT trial (NCT02773238). All received concurrent chemoradiation using functional lung avoidance planning, while 21/39 received consolidation durvalumab ICI. Within tumour-subtracted lung regions, 110 radiomics features (shape, intensity, texture) were extracted on pre-treatment [99mTc]MAA SPECT/CT perfusion (PERF) images using fixed-bin-width discretization. The performance of functional lung radiomics for pneumonitis (CTCAEv4 grade 2 or higher) risk stratification was benchmarked against previously reported lung dosimetric parameters and clinical risk factors. Multivariate least absolute shrinkage and selection operator (LASSO) Cox models of time-varying pneumonitis risk were constructed, and prediction performance was evaluated using optimism-adjusted concordance index (c-index) with 95% confidence interval reporting throughout.Results: Pneumonitis occurred in 16/39 (41%) patients. Among clinical characteristics and anatomic/functional lung dosimetry variables, only the presence of baseline chronic obstructive pulmonary disease (COPD) was significantly associated with the development of pneumonitis (HR 4.59 [1.69-12.49]) and served as the primary prediction benchmark model (c-index 0.69 [0.59-0.80]). Discrimination of time-varying pneumonitis risk was numerically higher when combining COPD with perfused lung radiomics size (c-index 0.77 [0.65-0.88]) or shape feature classes (c-index 0.79 [0.66-0.91]) but did not reach statistical significance compared to benchmark models (p>0.26). COPD was associated with perfused lung radiomics size features, including patients with larger lung volumes (AUC 0.75 [0.59-0.91]). Perfused lung radiomic texture features were correlated with lung volume (adj R2=0.84-1.00), representing surrogates rather than independent predictors of pneumonitis risk.Conclusions: In patients undergoing chemoradiation with functional lung avoidance therapy and optional consolidative immune checkpoint inhibitor (ICI) therapy for LA-NSCLC, the strongest predictor of pneumonitis was the presence of baseline chronic obstructive pulmonary disease. Our results support functional lung radiomics as surrogates of COPD. Further study of clinical, dosimetric, and radiomic feature combinations for radiation and immune-mediated pneumonitis in larger patient populations is warranted.