Incidence of Radiation Pneumonitis Among Patients Treated with Concurrent Thoracic Radiotherapy and Osimertinib for Metastatic Non-Small Cell Lung Cancer

Abstract

<h3>Purpose/Objective(s)</h3> A case series from China published in 2020 reported a high rate of radiation pneumonitis (RP) among 11 patients treated with concurrent thoracic radiotherapy (TRT) and osimertinib, including 9% who developed a fatal complication. We analyzed the RP rates for patients at our institution who were also treated with a similar combination for metastatic non-small cell lung cancer (NSCLC). <h3>Materials/Methods</h3> This retrospective study was performed at a single academic medical center in the US. We identified all patients who were treated with concurrent TRT and osimertinib between June 2016 and December 2021. Baseline patient characteristics, tumor size and location, and dosimetric parameters were evaluated. The highest grade of RP that developed within 6 months of treatment was scored in accordance with CTCAE v5.0. Fisher's exact test and logistic regression were performed to investigate the association of pre-treatment factors with development of grade ≥2 and grade ≥3 RP. <h3>Results</h3> Sixteen patients with metastatic NSCLC were treated with concurrent TRT and osimertinib over the study time period. The treatment site of each patient's pulmonary metastases was as follows: peripheral in 4 (25%), central in 4 (25%) (within 1-2 cm of the proximal bronchial tree [PBT]), ultra-central in 7 (44%) (within 1 cm of the PBT), and mediastinal in 1 (6%). Two of 16 patients withheld osimertinib 24-48 hours before and after TRT, both of which had tumors in an ultra-central location. Patients were treated with a median dose of 50 Gy (11-65 Gy) in a median of 7.5 fractions (1-15 fractions); the median duration of TRT was 10 days (1-22 days). The median follow-up time was 13 months (1 – 61 months). Nine patients developed grade ≥2 RP (56%) with a median time to onset of 29 days (1-84 days). The severity of RP was grade ≥3 in 6 (37.5%) and grade 4 in 1 (6.3%); no patients had grade 5 RP. Of the 6 patients who developed grade ≥3 RP, 2 (33.3%) were treated with stereotactic body radiotherapy (SBRT) while 4 (66.6%) were treated with hypofractionated TRT. All patients who developed grade ≥3 RP were female. Tumor location for patients who developed grade ≥3 RP was central in 3 (50%), ultra-central in 2 (33%) and mediastinal in 1 (17%); no patients with peripheral tumors developed grade ≥3 RP. Both patients who withheld osimertinib before and after TRT did not develop RP. The association of female sex and non-peripheral tumor location with grade ≥3 RP was not statistically significant in the context of a small case series (p=0.23). RP was not associated with the use of SBRT vs hypofractionated TRT or mean lung dose. <h3>Conclusion</h3> TRT with concurrent osimertinib was associated with a high rate of RP, particularly when the site of pulmonary metastases was in a central, ultra-central, or mediastinal location. Withholding osimertinib 24-48 hours before and after TRT may mitigate this risk. These data raise safety concerns that are not currently listed in treatment guidelines. Further research is indicated to validate these findings in larger cohorts.