Definitive Chemoradiotherapy Versus Total Laryngectomy Followed by Postoperative Therapy in Selected T3–T4a N0–N1 Laryngeal Cancer: Comparative Outcomes

Background/Objectives: Management of locally advanced laryngeal squamous cell carcinoma remains controversial. This study compared definitive chemoradiotherapy (CRT) with total laryngectomy followed by postoperative radiotherapy with or without chemotherapy (TL + PORT/CRT) in T3–T4aN0–N1 disease. Methods: This multicenter retrospective cohort included 311 patients treated between 2008 and 2025 at two centers: 160 received definitive CRT and 151 underwent TL + PORT/CRT. Survival was estimated using Kaplan–Meier and Cox regression analyses. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were used as adjusted analyses. The primary endpoint was disease-specific survival (DSS). Results: Median follow-up was 98 months. In the unmatched cohort, 5- and 10-year DSS rates were 92.1% and 92.1% after CRT versus 93.7% and 83.5% after TL + PORT/CRT (p = 0.351), while 5-year local control favored TL + PORT/CRT (98% vs. 79%; p < 0.001). After PSM (59 patients per group), cluster-robust Cox analysis showed inferior overall survival (OS) after CRT (hazard ratio [HR], 2.08; 95% confidence interval [CI], 1.12–3.86; p = 0.021) and inferior local control (HR, 12.83; 95% CI, 3.75–43.87; p < 0.001). In the 2015–2025 intensity–modulated radiotherapy (IMRT)-restricted analysis, OS also favored TL + PORT/CRT (HR, 3.64; 95% CI, 1.09–12.22; p = 0.036), whereas full-cohort IPTW showed no significant OS difference (HR, 0.93; 95% CI, 0.64–1.36; p = 0.715). Functional laryngeal preservation was achieved in 126/160 patients (78.8%) after CRT. Conclusions: Definitive CRT was associated with inferior local control, while DSS remained comparable. OS estimates varied across adjusted analyses and did not support a stable treatment-specific survival effect. Definitive CRT remains an organ-preservation option in appropriately selected patients.