PURPOSE: Stereotactic body radiation therapy (SBRT) is a promising therapeutic approach for inoperable, small (≤3 cm) primary lung cancer. However, the efficacy and safety of risk-adapted SBRT for treating large (>
3 cm) primary lung cancer remains inadequately characterized. PATIENTS AND METHODS: Patients with large (>
3 cm) primary lung cancer, diagnosed either clinically or histologically, were recruited between November 1, 2010 and December 31, 2022. Risk-adapted SBRT was administered in fractions (median, 5) for a total dose of 60 Gy (range, 45-63 Gy). The primary endpoint was overall survival (OS), and secondary endpoints included progression-free survival (PFS), local failure (LF), regional failure (RF), distant metastasis (DM), cancer-specific mortality (CSM), and toxicity. Differences in baseline characteristics were balanced via propensity score matching (PSM) with the logistic regression model, as well as 1:1 ratio matching and inverse probability of treatment weighting (IPTW). The Cox proportional hazards model was used for univariate and multivariate analyses aimed at identifying prognostic factors influencing OS and PFS. RESULTS: The 126 enrolled patients included 61 cases (48.4 %) diagnosed clinically and 65 cases (51.6 %) diagnosed pathologically. Following PSM and IPTW, no differences were found between patients diagnosed clinically versus pathologically in OS, PFS, tumor failure, and CSM. Univariate and multivariate analyses identified a Charlson comorbidity index ≥5 as an adverse prognostic factor for OS and PFS. One patient (0.8 %) in the pathologically diagnosed group developed grade 5 pneumonitis 2 months after undergoing SBRT. CONCLUSIONS: Risk-adapted SBRT may be an optimal treatment for appropriately selected patients with a large (>
3 cm) primary lung cancer lacking histologic confirmation.