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Importance: Distant metastasis (DM) remains the leading cause of death in patients treated for human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC). An effective treatment strategy needs to address DM while reducing treatment-related toxic effects., Objective: To assess DM-free survival in patients with HPV-OPSCC treated with neoadjuvant chemotherapy followed by transoral robotic surgery (NECTORS) and neck dissection compared with standard of care, concurrent chemoradiation (CCRT)., Design, Setting, and Participants: This multicenter retrospective cohort study compares prospective data from the NECTORS treatment group with a historical cohort of patients treated with CCRT. Patients with American Joint Committee on Cancer seventh edition stage III and IVa HPV-OPSCC treated with NECTORS and CCRT between February 2010 and September 2021 were included. Data were analyzed in September 2024., Exposures: Patients in the NECTORS arm were treated with 3 cycles of neoadjuvant docetaxel and cisplatin followed by TORS and neck dissection. Patients in the radiation therapy arm were treated with concurrent high-dose cisplatin and radiotherapy., Main Outcomes and Measures: DM-free survival was analyzed with Kaplan-Meier and Cox regression after adjusting for age, sex, tobacco and alcohol use, site, and cancer stage., Results: Of 342 included patients, 282 (82.5%) were male, and the mean (SD) age was 61.4 (9.4) years. A total of 232 patients were treated with CCRT and 110 patients were treated with NECTORS. Within the CCRT arm, 11 patients (4.7%) had locoregional recurrence (LRR), 5 (2.2%) had LRR and DM, and 28 (12.1%) developed distant-only metastasis. For patients treated with NECTORS, 5 (4.5%) developed LRR, 1 (0.9%) developed LRR plus DM, and no patients developed distant-only metastasis. With pseudorandomization matching for T and N stages, 209 patients were matched between the 2 treatment groups for further analysis (105 in the CCRT treatment arm and 104 in the NECTORS arm). The median (range) follow-up period for the CCRT and NECTORS groups were 5.8 (3.8-7.5) years and 5.1 (4.0-5.9) years, respectively. The hazard ratio of developing distant recurrence in the CCRT group was 10.77 (95% CI, 1.40-82.90) in univariate analysis and 9.98 (95% CI, 1.29-77.29) in multivariable analysis. In Kaplan-Meier survival analysis, the risk of developing DM was higher in the CCRT group. The hazard ratio for failure anywhere in the CCRT group was 3.32 (95% CI, 1.23-8.97) in univariate analysis and 3.21 (95% CI, 1.18-8.72) in multivariable analysis., Conclusions and Relevance: In this study, neoadjuvant chemotherapy followed by transoral robotic surgery and neck dissection was an effective treatment option for patients with stage III and IVa HPV-OPSCC. Findings from our study suggest lower rates of DM with NECTORS worthy of further investigation in prospective randomized trials.

Importance: Efforts are underway to deintensified treatment protocols for patients with human papillomavirus virus-associated oropharyngeal squamous cell carcinoma (HPV-OPSCC) to achieve similar excellent oncologic outcomes while reducing treatment-related adverse effects. Transoral robotic surgery (TORS) as primary treatment often requires adjuvant therapy due to the high incidence of nodal metastasis. Treatment with neoadjuvant chemotherapy followed by TORS and neck dissection (NECTORS), reserving radiation therapy for salvage, yields excellent oncologic outcomes., Objective: To assess patient-reported quality of life (QOL) and functional outcomes among patients with HPV-OPSCC who undergo NECTORS., Design, Settings, and Participants: This was a multicenter prospective cohort study of patients with HPV-OPSCC treated with the NECTORS protocol in 2017 to 2022. Consecutive patients with stage III or IVa HPV-OPSCC treated with NECTORS in 2017 to 2022 who had completed the primary QOL questionnaire at baseline and at least once during the 24-month follow-up period were included. Ninety-four patients were eligible, and 67 were included in the analyses., Outcome Measures: QOL questionnaires at baseline, and at month 1, 3, 6, 12, 18, and 24 posttreatment. Global score on the 30-item European Organization for Research and Treatment of Cancer Core quality of life questionnaire (EORTC QLQ-C30) was the primary outcome; the head and neck extension module (EORTC QLQ-HN35); the MD Anderson Dysphagia Inventory for dysphagia-related QOL; and the Decision Regret Scale were also used. Paired t tests assessed change between the baseline and 12- or 24-month patient-reported outcomes., Results: Among the study population of 67 patients (median [range] age, 63 [58-67] years; 54 [80.6%] male) with HPV-OPSCC, the most frequent cancer subsites were palatine tonsil (41 [61%]) and base of tongue (26 [39%]); none required adjuvant RT. Global QOL at 24 months improved compared with baseline (mean difference, 9.49; 95% CI, 2.45 to 16.53). All EORTC QLQ-C30 functional scores returned to baseline or improved within 3 to 6 months posttreatment and remained stable at 24 months. EORTC QLQ-HN35 symptom scale scores improved or were stable at 24 months. The MD Anderson Dysphagia Inventory scores demonstrated no significant difference between baseline and month 12 for global scores (mean difference, 6.15; 95% CI, -4.18 to 16.49) and composite scores (mean difference, 2.73; 95% CI, -1.62 to 7.09). Median (range) score on the Decision Regret Scale was 5 of 100 (0-30), representing mild overall regret., Conclusion and Relevance: The findings of this multicenter cohort study indicate that use of the NECTORS protocol is associated with excellent QOL outcomes. QOL measures returned to baseline levels or were better than baseline, which represents positive outcomes for patients with HPV-OPSCC who undergo this treatment regimen.