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

Abstract

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.

Transoral robotic surgery with neck dissection versus nonsurgical treatment in stage I and II human papillomavirus‐negative oropharyngeal cancer

“…Although oncologic outcomes appear to generally be equivalent between surgically based treatment and primary nonsurgical treatment in HPV‐associated OPC, this may not be the case in HPV‐negative OPC given the increased radioresistance in the latter 9,10 . Several recent institutional and national analyses of patients with HPV‐negative OPC indicate generally favorable outcomes with surgically treated patients, including improved survival versus primary chemoradiation therapy patients with T1‐T2N1‐N2b disease 12,16–19 . This national review represents a complimentary analysis of the cohort of patients with T1‐T2N0, HPV‐negative OPC.…”

“…The clinical factors predictive of TORS in this cohort were generally consistent with previous reports. Previously identified predictors of TORS versus nonsurgical treatment in OPC have included: younger age, race, female gender, higher comorbidity score, private insurance, tonsil primary site, smaller tumor stage, and decreasing nodal stage 12,19,20 …”

“…In a noncomparative study using the NCDB, Jackson et al reviewed 164 patients with T1‐4 HPV‐negative OPC undergoing TORS and found a 5‐year OS of 78%, including a 5‐year OS of 88% in the subgroup of patients with T1‐T2N0‐N1 disease 18 . There have been several national reviews utilizing the NCDB and/or SEER that have generally demonstrated improved survival outcomes in patients undergoing TORS versus nonsurgical treatment 12,19 . In 2018 Mahmoud et al reviewed 515 patients in the NCDB with T1‐T4 HPV‐negative disease and found a survival advantage in HPV‐negative patients treated with TORS versus those who received at least 50 Gray of primary radiation therapy +/− chemotherapy (3 year OS: 84% vs. 66%, respectively) 19 .…”

“…In light of this, retrospective national databases like the National Cancer Database (NCDB) may provide the best available information on comparative outcomes at this time 11 . Recently, treatment intensification with surgery + adjuvant therapy was shown to have superior survival versus primary nonsurgical treatment in T1‐T2, N1‐N2b HPV‐negative OPC in the NCDB and Surveillance, Epidemiology and End Results database (SEER) 12 . However, there is a paucity of information on comparative outcomes of TORS versus nonsurgical treatment in early stage tumors without clinical evidence of nodal disease 13 .…”

Current Therapeutic Strategies in Patients with Oropharyngeal Squamous Cell Carcinoma: Impact of the Tumor HPV Status

“…In a retrospective multicentric analysis of 371 patients with a p16-negative locally advanced OPSCC, Culie et al showed that upfront surgery was significantly associated with improved OS (p = 0.01), DSS (p = 0.02), and RFS (p = 0.02), compared with non-surgical treatment (5-year OS: 71.9 vs. 46.5%; DSS: 76.8 vs. 57.7%; RFS: 60.2 vs. 42.2%) [15]. In another retrospective study involving 3674 patients with an HPV-negative stage III-IVa (T1-2, N1-2b, and M0) OPSCC from the American National Cancer Database and Surveillance, Epidemiology, and End Results (SEER) program between 2010 and 2016, Jacobs et al showed that, on weighted multivariable Cox regression, patients recommended to receive frontline surgery had improved OS compared with those recommended to receive CRT alone (HR = 0.77; 95% CI: 0.68-0.86) [82]. Altogether, these data support the use of upfront surgery with risk-based addition of adjuvant therapy in patients with HPV-negative locally advanced OPSCC [10].…”