Matched-Pair Analysis of Survival in the Patients with Oropharyngeal Squamous Cell Carcinoma Treated with Radiotherapy or Concurrent Chemoradiotherapy Versus Surgical-Based Treatment

Background: This study compared survival outcomes between upfront surgery +/−radiotherapy (RT) and definitive RT with or without chemotherapy (RT/CRT) in HPV-negative oropharyngeal squamous cell carcinoma (OPSCC). Methods: A retrospective matched-pair analysis included 150 patients treated between 1990 and 2020. Fifty (RT/CRT) cases (2009–2020) were matched 2:1 to 100 surgical cases (1990–2009) by sex, subsite, T/N classification, and AJCC 8th stage. Sixty-six percent of surgically treated patients received adjuvant RT. Only HPV-negative tumors confirmed by p16 and HPV DNA testing were analyzed. Survival was assessed with Kaplan–Meier and Cox regression. Results: RT/CRT achieved significantly higher 5-year overall survival (59% vs. 28%) and disease-specific survival (69% vs. 45%) compared with surgery. Matched-pair analysis showed increased overall mortality (HR 1.91; p = 0.008) and disease-specific mortality (HR 2.05; p = 0.022) in surgical patients. In stage III disease, RT/CRT provided markedly superior DSS (87% vs. 42%). No significant differences were found in local control or recurrence-free survival, but metastasis-free survival was significantly worse in the surgical cohort, and the incidence of second primary tumors was significantly lower in the RT/CRT group. Conclusions: These findings indicate that RT/CRT provides superior survival outcomes and better control of distant metastasis and second primary tumors compared with surgery in HPV-negative OPSCC, particularly in stage III disease. RT/CRT should be considered an effective organ-preserving option for this population.