Observation of Acute Toxicity Events in Lung Cancer Patients Treated Concurrently with a Tyrosine Kinase Inhibitor

Abstract

<h3>Purpose/Objective(s)</h3> Available tyrosine kinase inhibitors (TKI) for patients with non-small-cell lung cancer (NSCLC) have long half-lives. If thoracic radiation is given, it can be impractical to hold the TKI long enough for a washout. We set out to determine whether patients taking a TKI are at elevated risk for acute esophageal, pulmonary, or cardiac toxicity following thoracic radiation. <h3>Materials/Methods</h3> We performed a single-institution retrospective study of patients who had lung radiation from March 2011 to December 2021. Concurrent TKI use was defined as drug use within 3 months before or after radiation. Patients completed palliative or definitive thoracic radiation courses (including SBRT) for any primary lung cancer. Radiation doses and dosimetric parameters (esophagus mean and V30, heart mean and V25, lung mean and V20) were converted to biologically effective doses (BED₁₀) using an a/b ratio of 10 Gy. CTCAE acute toxicity outcomes were determined within 12 months of completion of radiation and compared using chi-square tests, Fisher's exact tests, and multivariate logistic regressions. <h3>Results</h3> A total of 105 patients receiving lung radiation were identified with median follow up of 12 months (range 0.6–114 months). Histologies included adenocarcinoma (51.4%), squamous cell carcinoma (23.8%), other NSCLC (15.2%), and SCLC (9.5%). 33 patients (31.4%) had metastatic disease at the time of radiation treatment. Median dose was 72 BED₁₀ Gy (range 15.7 to 151.2 BED₁₀ Gy). A total of 14.3% (n=15/105) of patients received concurrent TKI. The rate of grade 2-3 acute esophagitis was 20.0% (18/90) and 53.3% (8/15) for patients receiving radiotherapy without and with concurrent TKI, respectively (p = 0.006). There were no grade 4-5 esophagitis events. When controlling for mean esophageal dose and concurrent chemotherapy, concurrent TKI use was found to be an independent predictor for grade 2-3 esophagitis (OR = 6.91, 95% CI = 1.99 – 26.03, p = 0.003). Acute esophagitis was most frequently seen with osimertinib (4/7 = 57.1%), lorlatinib (2/2 = 100.0%), and crizotinib (2/3 = 67.7%). The rate of grade 2-3 pneumonitis was 5.6% (5/90) and 15.3% (2/13) without and with concurrent TKI, respectively (p = 0.261). On multivariate analysis, TKI use was not associated with pneumonitis. There were no acute grade 4-5 pneumonitis events or grade 2-5 cardiac toxicities. <h3>Conclusion</h3> This study raises the hypothesis that acute esophageal toxicity may be higher after radiation for patients receiving many of the most common TKIs. Thoracic radiation plays a crucial role in the management of NSCLC, and as the use of TKIs expands, it is critical to quickly identify potential complications associated with concurrent thoracic radiation.