Revisiting the Radiation Therapy Oncology Group 1221 Hypothesis: Treatment for Stage III/IV HPV‐Negative Oropharyngeal Cancer

OBJECTIVE: In 2014, the Radiation Therapy Oncology Group 1221 trial was initiated to analyze whether surgery with risk-based radiation therapy or chemoradiation therapy was superior to chemoradiation therapy alone in patients with clinically staged T1-2N1-2bM0 HPV-negative oropharyngeal squamous cell carcinoma. However, the study was prematurely terminated. Given the lack of a randomized controlled trial, we retrospectively approached the same question using large national cancer databases. STUDY DESIGN: Retrospective cohort study. SETTING: The National Cancer Database and Surveillance, Epidemiology, and End Results (SEER) program from 2010 to 2016. METHODS: We identified 3004 patients in the National Cancer Database and 670 patients in the SEER database. Statistical techniques included Kaplan-Meier survival analysis, binary and multinomial logistic regressions, Cox proportional hazard regressions, and inverse propensity score weighting. RESULTS: On weighted multivariable Cox regression, patients recommended to receive frontline surgery had improved overall survival as compared with those recommended to receive chemoradiation therapy alone (hazard ratio [HR], 0.77; 95% CI, 0.68-0.86). On post hoc multivariable analysis based on therapy actually received, frontline surgery with adjuvant chemoradiation therapy was associated with improved overall survival (HR, 0.59; 95% CI, 0.50-0.71) as compared with chemoradiation therapy without surgery. Analysis of the SEER cohort revealed improved overall survival (HR, 0.69; 95% CI, 0.54-0.87) and head and neck cancer-specific survival (HR, 0.59; 95% CI, 0.41-0.84) in patients recommended to receive frontline surgery over chemoradiation therapy alone. CONCLUSION: Our findings support the use of surgery with risk-based addition of adjuvant therapy in patients with cT1-2N1-2bM0 HPV-negative oropharyngeal cancer.