Abstract Purpose: The decline in survival of patients diagnosed with laryngeal cancer over the past two decades has been associated with a rise in nonsurgical management for stage III/IV disease following results from the VA Larynx Trial and RTOG 91-11. To clarify the potential driving factors for the decrement in outcomes, this analysis assesses patterns of use and overall survival (OS) amongst the primary NCCN-recommended modalities of therapy stratified by T-stage and radiation (RT) dose. Methods: The National Cancer Data Base was used to identify 11,551 patients with stage T2N+ 1-3 or T3-4N0-3-any glottic/supraglottic SCC squamous cell carcinoma (SCC) treated between 2003-2011 with total laryngectomy (TL) or definitive chemoradiation (CRT). Treatment modality was divided into concurrent CRT, TL alone, and TL + with adjuvant RT/CRT (TL+A). Kaplan-Meier method was used to estimate OS for each treatment group. Hazard ratios (HR) with 95% confidence intervals (CI) were computed using Cox regression modeling, adjusting for date of treatment, treatment facility (community vs. academic), age, gender, race, insurance status, tumor grade, T-stage, and Charlson-Deyo comorbidity score. Results: The median follow-up was 29.6 months for the entire population and 42.6 months for surviving patients. Among this cohort, the use of CRT increased from 63.92% to 88.75% for T2, 60.74% to 88.75% for T3, and 43.28% to 44.15% for T4 tumors; the use of TL for T2/-3 tumors had a correlative decline, while there was a modest increase of TL for T4 from 47.06% to 50.49. With 5,800 deaths reported, the estimated 3 and 5/5-year OS for CRT, TL, and TL+A was 60.6/47.1%, 56.5/46.4%, and 63.3/50.8%, respectively (omnibus p < 0.0001). Compared to CRT, the adjusted HR (95% CI) for OS for TL and TL+A was 1.0 (0.90-1.11, p=0.98) and 0.81 (0.74-0.89, p<0.0001), respectively. When including only patients treated with an optimal RT dose (i.e. ≥70-74 Gy, 58.5-65.25 in 2.25 Gy/fx, or 79.2 Gy in 1.2 Gy/fx BID), the adjusted HR (95% CI) for TL and TL+A compared to optimal CRT was 1.06 (0.95-1.19, p=0.27) and 0.87 (0.78-0.96, p=0.005), respectively. However, after excluding all patients with T4-tumors, the benefit of TL+A over CRT was lost, as the adjusted HR (95% CI) for OS for S and S+A compared to any CRT was 1.07 (0.94-1.23, p =0.31) and 1.03 (0.91-1.17, p=0.66), respectively, and compared to an optimal CRT regimen only was 1.12 (0.97-1.29, p =0.11) and 1.07 (0.94-1.22, p=0.32), respectively. Conclusion: In this population-based cohort, CRT and S+A resulted in equivalent OS for T2N+ 1-3 and T3N-0-3any glottic/supraglottic SCC. However, when including T4 patients in this analysis, S+A was associated with better OS compared to CRT, even after including only optimal RT regimens. Given a relatively steady use of larynx-preservation for T4 tumors over this time, these results suggest that the OS decline seen with laryngeal cancer may be driven by T4-tumors treated with larynx-preservation CRT. Citation Format: Sagar A. Patel, Muhammad M. Qureshi, Kimberly Mak, Nicholas J. Giacalone, Scharukh Jalisi, Gregory Grillone, Minh Tam Truong. Optimizing patient selection for total laryngectomy versus larynx-preservation chemoradiotherapy for locally advanced laryngeal squamous cell carcinoma: An analysis of the National Cancer Data Base [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 25.