Expanded HILUS Trial: A Pooled Analysis of Risk Factors for Toxicity From Stereotactic Body Radiation Therapy of Central and Ultracentral Lung Tumors

Abstract

Stereotactic body radiation therapy (SBRT) for tumors near the central airways implies high-grade toxic effects, as concluded from the HILUS-trial. However, the small sample size and relatively few events limited the statistical power of the study. We therefore pooled data from the prospective HILUS-trial with retrospective data from patients in the Nordic countries treated outside the prospective study to evaluate toxicity and risk factors for high-grade toxic effects. All patients were treated with 56 Gy in 8 fractions. Tumors within 2 cm of the trachea, the mainstem bronchi, the intermediate bronchus or the lobar bronchi were included. Primary endpoint was toxicity and secondary endpoints were local control (LC) and overall survival (OS). Clinical and dosimetric risk factors were analyzed for treatment-related fatal toxicity in univariable and multivariable Cox regression analyses (UVA and MVA). Of 230 patients evaluated, grade 5 toxicity developed in 30 patients (13%) whereof 20 patients suffered fatal bronchopulmonary bleeding. The MVA revealed tumor compression of the tracheobronchial tree and maximum dose to the mainstem or intermediate bronchus as significant risk factors for grade 5 bleeding and grade 5 toxicity. The 3-year LC and OS-rates were 84% (95% CI=80-90%) and 40% (95% CI=34-47%), respectively. Tumor compression of the tracheobronchial tree and high maximum dose to the mainstem or intermediate bronchus increase the risk of fatal toxicity after SBRT in 8 fractions for central lung tumors. Similar dose constraints should be applied to the intermediate bronchus as to the mainstem bronchi.