Optimizing Lung SBRT Dose while Accounting for Histology Ensures Optimal Local Control for Inoperable Stage I Non-Small Cell Lung Cancer: Can Higher Biologically Equivalent Dose Overcome Size and SUV?

Abstract

<h3>Purpose/Objective(s)</h3> Retrospective studies suggest that increasing tumor size, PET avidity and squamous histology unfavorably impact local failure (LF) after lung SBRT. We sought to characterize the interaction of SBRT dose with these variables known to be associated with LF. <h3>Materials/Methods</h3> We identified 1,573 consecutive patients treated with definitive intent SBRT for stage I NSCLC from 2003-2020 from an IRB-approved institutional prospective registry. We utilized competing risk regression, with death as a competing event, to identify patient, tumor and treatment factors associated with the endpoints LFand any failure (AF), and Cox proportional hazards regression for overall survival (OS). <h3>Results</h3> Median tumor size was 2.2 cm and PET SUV 7.5. Histology was adenocarcinoma in 30.6%, squamous cell in 27.8%, NSCLC NOS in 7.3%, non-diagnostic in 9.7% and unbiopsied in 24.3%. 52.3% of patients were female; 5% never smokers, 72.7% former smokers, and 22.3% active smokers. 64% completed mediastinal staging and 93.9% were medically inoperable. Median Charlson score was 6, and median age 74.7 years. SBRT regimen was 30/1 in 5%, 34/1 in 21%, 48-50 Gy/4-5 in 46%, 54-60/3 in 24% and 50-60 Gy/8-10fx in 3%. With a median follow-up of 22.9 months 7.9% of patients had LF and 31.2% had AF 31.2%. Median OS was 35.4 months. On univariate analysis, squamous histology had a higher risk for LF vs. adenocarcinoma (HR=2.15, p=0.001). There was no difference in LF for NSCLC NOS (HR= 0.85, p=0.71) and un-biopsied patients (HR= 1.23, p=0.40) vs. adenocarcinoma. Other factors associated with increased risk of LF were tumor size (p<0.0001), metabolic activity (p<0.0001), and lower BED radiation dose (48-50 Gy/4-5 fx, BED 100-105, HR=3.56, p<0.0001). Single fraction radiation (BED 149.6) had similar LF compared to 54-60 Gy/3 fx (BED 150-180). On multivariable analysis, tumor size and metabolic activity were no longer statistically significant, leaving squamous histology (HR=1.92, p=0.0086) and lower BED radiation (48-50 Gy/4-5 fx, HR=3.07, p=0.002) as significant correlates. On multivariable analysis for AF, tumor size and metabolic activity were significantly associated with AF, while SBRT dose and squamous histology were not statistically significant. A broad range of correlates with OS were identified (age, gender, ethnicity, KPS, Charlson score, hemoglobin level, tumor size, PET SUV, histology, and SBRT dose). <h3>Conclusion</h3> While tumor size, PET avidity, squamous histology and SBRT dose were univariate correlates for LF, only squamous histology and SBRT dose remained significant on multivariate analysis. Squamous histology appears to be an independent driver of LF. Higher SBRT dose (54-60 Gy/3fx, 34 Gy/1 fx, BED >149) may overcome other correlates to LF (size, SUV), though these remain as the strongest correlates to distant recurrence.