Stereotactic ablative radiotherapy in operable stage I NSCLC patients: Long-term results of the expanded STARS clinical trial.
Authors: Chang Joe Y. , Mehran Reza J. , Feng Lei , Balter Peter , McRae Stephen , Berry Donald A. , Roth Jack A. ,   STARS Clinical Trials Group
Published: June 2021

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Background: We published a pooled analysis of 2 randomized trials (STARS/ROSEL) that compared lobectomy with mediastinal lymph node dissection (L-MLND) vs stereotactic ablative radiotherapy (SABR) in operable stage I NSCLC. There were no significant differences in disease progression but significantly higher 3-year overall survival (OS) in the SABR arm (95% vs 79%). Owing to concerns regarding the small sample size (n = 58), short follow-up (3 years), and non-uniform use of video-assisted thoracoscopic surgery (VATS), we expanded the STARS protocol to a single-arm SABR trial with a protocol-specified comparison to a published, longitudinally-followed institutional cohort of stage IA NSCLC status post VATS L-MLND (n = 229). Methods: Inclusion criteria were stage IA NSCLC (≤3 cm, N0M0 and staged by PET/CT with EBUS) with Zubrod performance status (PS) 0-2, baseline FEV1 > 40% and DLCO > 40% and deemed operable by a multidisciplinary team. SABR utilized 4-dimensional CT simulation and volumetric image guidance; 54 Gy in 3 fractions were delivered to planning target volumes (PTVs) located peripherally, or 50 Gy in 4 fractions to more central PTVs. All patients were followed by chest CT every three months for the first two years, every 6 months for another three years, and then annually. Non-inferiority of SABR could be claimed if the 3-year OS was not lower than the historical VATS L-MLND cohort by more than 12%. We conducted a risk-factor matched comparison study of the primary outcome between the SABR and the historical VATS L-MLND. Results: The median follow-up among the 80 SABR patients was 61 months (range, 34-79 months). The OS and progression-free survival (PFS) were 91% (95% CI: 85̃98%) and 80% (95% CI: 72̃89%) at 3 years, and 87% (95% CI: 79̃95%) and 77% (95% CI: 68̃87%) at 5 years, respectively. The 5-year cumulative incidence rate counting death as competing risk was 6.3% (95% CI: 2.3̃13.2%) local, 12.5% (95% CI: 6.4̃20.8%) regional, and 8.8% (95% CI: 3.8̃16.2%) distant (any recurrence 17.6% (95% CI: 10.1̃26.7%)). The 5 year cumulative incidence rate of second lung primary was 6.9% (95% CI: 2.5̃14.6%). There were 1.3% grade 3 and no grade 4-5 toxicities. The propensity score matched (age, gender, tumor size, histology, PS) comparison of SABR vs VATS L-MLND revealed no significant differences in PFS (p = 0.063), lung cancer-specific survival (p = 0.075), or cumulative incidence rates of local (p = 0.54), regional (p = 0.97), or distant failures (p = 0.33). The SABR arm was associated with significantly higher OS (91% vs 82% at 3 years and 87% vs 72% at 5 years; p = 0.012 from log-rank test). The hazard ratio was 0.411 (95% CI: 0.193̃0.875; p = 0.021). Conclusions: The long-term OS and PFS of SABR is not inferior to VATS L-MLND for operable stage IA NSCLC. SABR remains a promising approach for this population, but multidisciplinary management is strongly recommended. Clinical trial information: NCT02357992.