Quantitative Evaluation of Normal Lung Density Changes in Non-Small Cell Lung Cancer Patients Treated With Radiotherapy and PD-1 Immune Checkpoint Inhibitors.

PURPOSE/OBJECTIVE(S) Radiographic density changes in normal lung parenchyma are a function of radiation dose, are associated with inflammation, and vary among patients. The purpose of this study is to evaluate these radiation-induced changes quantitatively in different patient cohorts treated with PD-1 Immune Checkpoint Inhibitors (ICI) and investigate them as possible RT-related imaging biomarker for outcome. MATERIALS/METHODS We looked at two groups of non-small cell lung cancer (NSCLC) patients drawn from two institutions: patients with metastatic disease treated with non-curative intent and normal lung in the radiation field, and patients receiving definitive chemo-radiation (CRT) followed by adjuvant PD-L1 blockade (durvalumab), some of which received durvalumab also concurrently. Normal lung parenchyma on the first post-treatment chest computer tomography (CT) scans (median time 3 months post RT) was deformably registered to the treatment plan to analyze lung density changes as function of dose, normalized to 2Gy-equivalent, and quantified as Hounsfield Unit (HU)/Gy. Differences between groups were assessed using Wilcoxon's rank sum test, correlation to progression-free and overall survival using Cox regression. RESULTS We analyzed a total of 26 patients treated with non-curative intent RT and 60 patients who received CRT. For metastatic patients, RT delivered concurrently with ICI (n = 16) led to significantly larger changes compared to patients receiving RT before initiation of ICI (median 2.21 vs 0.27 HU/Gy, P = 0.02), even though the former received significantly lower doses to the normal lung (median 27.6 vs 55.8 Gy, P = 0.02). Fraction sizes were smaller when RT was delivered concurrently with ICI (median 3.3 vs 5.5 Gy/fraction). Number of patients and events in metastatic patients were too low for survival analysis. During CRT, patients receiving concurrent durvalumab (n = 20) did not show significant lung density changes compared to those that did not (median 1.39 vs 1.28 HU/Gy, P = 0.99). All CRT patients received 1.8-2.2 Gy/fraction. The amount of change in each patient did not correlate with progression-free or overall survival (HR = 0.91, 95% CI [0.71-1.16] and HR = 0.92, [0.72-1.17] respectively). CONCLUSION RT delivered concurrently with PD-1 ICI leads to significantly increased normal lung density changes in metastatic patients but not in locally advanced patients treated with CRT, possibly related to the different fraction size. For CRT patients treated with adjuvant durvalumab, normal lung changes after CRT do not correlate with outcome. The correlation of lung density changes to oncologic outcomes in metastatic patients' needs to be studied in larger cohorts.